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Current challenges in treatment options for visceral leishmaniasis in India: a public health perspective
Om Prakash Singh1,
Bhawana Singh1,
Jaya Chakravarty1 &
Shyam Sundar1
Infectious Diseases of Poverty volume 5, Article number: 19 (2016) Cite this article
Visceral leishmaniasis (VL) is a serious parasitic disease causing considerable mortality and major disability in the Indian subcontinent. It is most neglected tropical disease, particularly in terms of new drug development for the lack of financial returns. An elimination campaign has been running in India since 2005 that aim to reduce the incidence of VL to below 1 per 10,000 people at sub-district level. One of the major components in this endeavor is reducing transmission through early case detection followed by complete treatment. Substantial progress has been made during the recent years in the area of VL treatment, and the VL elimination initiatives have already saved many lives by deploying them effectively in the endemic areas. However, many challenges remain to be overcome including availability of drugs, cost of treatment (drugs and hospitalization), efficacy, adverse effects, and growing parasite resistance. Therefore, better emphasis on implementation research is urgently needed to determine how best to deliver existing interventions with available anti-leishmanial drugs. It is essential that the new treatment options become truly accessible, not simply available in endemic areas so that they may promote healing and save lives. In this review, we highlight the recent advancement and challenges in current treatment options for VL in disease endemic area, and discuss the possible strategies to improve the therapeutic outcome.
Please see Additional file 1 for translations of the abstract into the six official working languages of the United Nations.
More than 1 billion people are affected by one or more neglected infectious diseases worldwide [1, 2], for which we lack effective, affordable, and easy to use drugs as well as other control methods. Visceral leishmaniasis (VL), also known as kala-azar, is one of the disorders in this group caused by a protozoan parasite, L. donovani and/or L. infantum, which is transmitted by the bite of an infected sand fly, Phlebotomus argentipes in the Indian subcontinent (ISC) [3]. VL results in prolonged fever, anemia, splenomegaly, wasting; and is fatal when left untreated [4]. There are approximately 200–400 thousands new cases every year occurring predominantly in just six countries: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil [5]. More specifically, >10,000 cases occur in India alone every year and the state of Bihar accounts for majority of these cases. These figures, however, do not reflect the true social impact of this disease because VL has a focal distribution which is devastating to the affected communities. The cost of treatment is important when patients need to pay for treatment as ~75 % of the VL cases in Bihar live below the poverty threshold of less than US $ 1.0 a day, and this is similar in other endemic countries although exact data are scarce [6]. Poverty seriously affects the prognosis of VL because most of the patients and their families have to pay for diagnosis, drugs and hospital care, and this is often half or more of the annual household income [7]. As a result, families with a VL infected member descend deeper into poverty.
VL has never been featured as high priority for drug development programs funded by the pharmaceutical industries because it disproportionately affects the poor people in developing countries and are unlikely to yield good returns on R&D costs. In 2005, the governments of India, Bangladesh and Nepal signed a joint memorandum of understanding to eliminate VL with the aim to reduce the incidence to less than 1 per 10,000 people at sub-district level by the year 2015 [8] which has recently been extended to the year 2017 [9]. Because of the anthroponotic nature of the transmission of L.donovani in the ISC, the use of quality drugs is not only a therapeutic tool, but also a tool for VL control. Indeed, human beings are the only known reservoir of L.donovani, therefore, identification and proper treatment of parasite carriers will reduce the parasite biomass and prevents onward transmission and deaths (Fig. 1). These factors urge for search of new, effective, less toxic and simplified treatments to replace or complement the few currently available drugs. Unfortunately, no new antileishmanial drugs are expected in near future, because very few drugs are in the R&D pipeline at various stages of development [10]. Furthermore, resistance to first line treatment has long plagued effective treatment of VL in India, making second line treatments and extended hospitalization more common. In India, about 5–10 % of patients with VL, after recovery of acute illness, may develop a chronic cutaneous form called Post kala-azar dermal leishmaniasis (PKDL) that requires prolonged and expensive treatment [11]. The emergence of HIV and its association with VL results in a deadly synergy. A significant number of patients in Bihar are living with HIV-VL co-infection [12], and we expect to see more HIV-VL co-infections in near future which will further generate major therapeutic challenges [13]. In the following sections, we have briefly reviewed the current treatment of VL in endemic areas of Bihar, India, and discuss the challenges and its possible solutions.
Schematic of intervention model based on VL chemotherapy
Treatment options for VL
There is no vaccine available for VL; hence control of VL exclusively depends on chemotherapy. Available treatment options for VL are limited and not up to satisfactory standards due to problem relating to efficacy, adverse effects, increasing drug resistance, high cost and need for hospitalization to complete the full dose of treatment. So far, many clinical trials have been done in India to optimize the therapeutic regimens and to protect the efficacy of limited number of available anti-leishmanials (Tables 1 and 2). A full list of completed, ongoing and proposed clinical trials for leishmaniasis in various parts of the world is available on clinical trial registry site (https://clinicaltrials.gov). Indeed, important recent advances have been made in the area of VL treatment that if implemented effectively could eliminate this disease from most endemic parts of the world. Table 3 lists the rank wise recommended dose of anti-leishmanial drugs for VL treatment.
Table 1 Currently available anti-leishmanial drugs for treatment of VL: product name, cure rate, mode of action on parasite, advantages and limitations
Table 2 Summary of studies and clinical trials on monotherapy in treatment of visceral leishmaniasis in India
Table 3 Recommended treatment regimens for VL in Indian subcontinent (ranked by preferences)
Pentavalent Antimonials
Past experiences have confirmed that response to a drug varies from region to region. For example, in hyper-endemic regions of India and adjoining areas of Nepal, pentavalent antimonials (Sbv also known as sodium stibogluconate) has lost its efficacy with the result that about two thirds of patients in some of these areas are refractory to Sbv treatment [14]. However, in Bangladesh, the situation is different as no resistance to Sbv has been officially reported. SbVwas recommended and used in Bangladesh till 2009 as a first line drug [15]. Moreover, Sbv are still the first-line drugs in many countries worldwide for all clinical forms. Major side effects are cardiac arrhythmias, prolonged QT interval, ventricular premature beats, ventricular tachycardia and ventricular fibrillation [16]. There are accumulating evidence suggesting that Sbv has a dual mode of action, and acts on both the parasite and the infected macrophage. Upon contact with infected macrophages, Sbv stimulates the macrophages to kill the intracellular parasites and when reaching the parasite, Sbv is reduced to SbIII, which can directly kill the parasite inside phagolysosome by inhibiting trypanothoine reductase (an enzyme that recycle oxidized trypanothione to keep the trypanothione in reducing state) [17]. Pentamidine, a diamidine compound, was the first drug to be used in Sbv refractory patients, and cured most patients initially, but after a decade its efficacy also declined from ~100 to 70 % in hyper-endemic areas of India.
Amphotericin B Dexoycholate (AmB)
Amphotericin B (AmB) was initially recommended in India for treatment of patient's refractory to Sbv [18, 19]. However, due to increasing unresponsiveness of Sbv in endemic areas, it is currently being used as first line drug for VL treatment. AmB formulated with sodium deoxycholate was the first parenteral amphotericin B preparation available commercially as Fungizone (Bristol-Meyer-Squibb). Several clinical trials have been conducted till date for treatment of VL involving AmB (reviewed in ref.[20, 21]) with excellent cure rate (~100 %) at dose of 0.75–1.0 mg/kg for 15–20 intravenous infusions [22, 23]. The drug has high safety and efficacy; however, prolonged hospitalization, adverse reactions like high fever with rigor and chills, and the need to close monitoring of renal functions and electrolyte levels are well-recognized drawbacks of AmB treatment (Table 2 enlists the studies in India with AmB). The mechanism of action of AmB is still not fully investigated but it is assumed that it interferes with the ergosterol in the cell membrane of Leishmania parasite, causing changes in the membrane permeability and leakage of intracellular components [24]. Cell death occurs in part because of these permeability changes, but other mechanisms may also contribute to AmB antifungal activity. AmB is not active in vitro against organisms that do not contain sterols in their cell membranes (e.g., bacteria). Binding to sterols in mammalian cells (e.g., certain kidney cells, erythrocytes) may be responsible for the toxicities associated with AmB (reviewed in ref. [25]).
Lipid formulations of Amphotericin B (L-AmB)
The advent of Liposome Technology in mid 1960s and subsequently its application for minimizing dose-limiting toxicity has added a new paradigm in AmB treatment, providing a highly effective and safe therapy for many forms of systemic mycosis. There are six lipid formulations of amphotericin B available commercially that differ from each other with respect to dose, efficacy and toxicities. These are: i) liposomal amphotericin B (AmBisome®; Gilead Sciences); ii) Amphotericin B lipid complex (Abelcet®; ENZON Pharmaceuticals Inc.); iii) AmB cholesteryl sulfate complex, also called AmB colloidal dispersion [ABLC] (Amphocil; Sequus Pharmaceuticals); iv) FUNGISOME™ (Lifecare Innovation Pvt Ltd); v) AmB emulsion (Amphomul, Bharat Serum and Vaccines, India); and vi) amphiphilic L-AmB (KALSOME™10, Life care Innovation, Pvt. Ltd, India). Among these, Ambisome® is tested in most of the clinical trials and is probably the most efficacious of all anti-leishmanial drugs currently available [26]. Most of the clinical trials of L-AmB for the treatment of VL have taken place in India, where more than 10 different regimens have been tested (Table 2). Most have been open-label, dose-finding studies or randomized controlled comparisons. Indian experience has demonstrated that L-AmB caused substantially less toxicity than conventional AmB or amphotericin B lipid complex (ABLC), but high cost is the major drawback. Much of research has been focused to reduce the course of L-AmB whilst retaining its efficacy, to limit the cost to patients. Sundar et al. showed that 15 mg/kg of Ambisome® (3 mg/kg on each of 5 injections) cured 96 % patients [27]. Later on in separate study by Thakur et al. [28], and Sundar et al. [27, 29, 30] have demonstrated the efficacy and safety of Ambisome® achieving efficacy rates in excess of 90 % in single doses of 5–15 mg/kg (Table 2), making it an excellent treatment option for VL in the ISC. Low toxicity of L-AmB has made it best treatment option for HIV-VL co-infection patients. In a study by Sinha et al., excellent long term survival and retention rate were obtained; however, relapse within 2 year remained frequent [31]. It can be given safely in doses as high as 30–40 mg/kg body weight in HIV-positive VL patients [32, 33]. It has been speculated that lipid formulations enhance uptake by macrophages (the site of parasite replication) which results in the localization of the drug in the macrophage abundant areas in the body. Ambisome® is currently being used as a first line drug for the treatment of VL in India, under the kala-azar elimination program.
Among other lipid formulations, Fungisome™ with the dose 7.5 mg/kg daily for 2 days showed 100 % cure rate (without any serious adverse effect) in an open label randomized study [34, 35]. Abelcet has shown cure rate 90–100 % at total dose of 10–15 mg/kg in SbV resistant patients [36]. Amphocil was evaluated at three different doses (7.0, 10 and 15 mg/kg) which showed final cure rate up to 97 % [37]. Amphomul (single dose: 15 mg/kg body weight) was found highly effective and safe for treatment of VL [38]. KALSOMETM is still not tested on human VL, however, in murine model with 7.5 mg/kg double dose results in almost complete clearance of parasites from both liver and spleen [39].
Paromomycin
Paromomycin is a broad-spectrum aminoglycoside antibiotic produced from culture filtrates of Streptomyces krestomyceticus and with activity against a variety of Gram-positive and negative organisms, mycobacteria, protozoa. The anti-leishmanial activity of paromomycin was first demonstrated in the 1960s [40, 41] and subsequently confirmed in vitro and in vivo [42]. This drug was first tested in Kenya in 1980s for treatment of human VL [43]. It was registered for treatment of patients with VL in India in 2006 by Gland Pharma Ltd., Hyderabad, India, who is now the sole manufacturer for intramuscular paromomycin worldwide [44]. Several clinical trials have been conducted in Kenya, Sudan and India [43, 45–48], and all these studies have reported that paromomycin, when used as a single agent or in combination with sodium stibogluconate was highly efficacious and well tolerated in the treatment of VL. High efficacy rates for paromomycin (i.m) injection (dose-11 mg/kg for 21 days) has been reported to 98.4 % with initial cure (defined as the initial response after complete treatment), and the final cure (defined as a complete response with no evidence of relapse up to 6 months after an initial cure of 21 days of treatment) was approximately 94.6 % [49]. Shortening the course of this drug from 21 to 14 days has subsequently shown inferior cure rate [50]. Pain at injection site, elevated liver function tests (LFTs); fever, proteinuria, vomiting, elevations in alkaline phosphatase and bilirubin values are the main adverse events associated with this drug. The mechanism of action of paromomycin is thought to be interference with protein synthesis in the ribosome of the target organism and inhibit the respiration [51].
Miltefosine
Miltefosine is an alkyl phospholipid compound was the first effective oral anti-leishmanial agent in VL, and registered for the treatment of VL in India in 2002, Germany in 2004, Colombia in 2005 and Bangladesh in 2006 (reviewed in ref. [52]). Miltefosine was originally intended for breast cancer and other solid tumours [53]. However, due to dose limiting gastro-intestinal toxicity, it could not be developed as an oral agent in cancer [54]. Evidence of excellent anti-leishmanial activity both in-vitro and in experimental animal models [55–57] prompted the clinical assessment of oral miltefosine in human VL in1996 [53]. Miltefosine was licensed for use in VL patients in India in 2002 following a Phase III clinical trial in which 94 % long term cure rate was observed in a dose 50–100 mg/day for 28 days [58]. It was licensed in Europe for treatment of HIV-VL co-infected patients in 2005 [59, 60]. However, because of its teratogenic effect in animals and its long-term residual persistence shown in humans, there is some concern on unrestricted use of the drug in women of child-bearing-age. Being orally administrable, miltefosine has a big advantage of domiciliary treatment. However, it has the drawback of poor compliance due to its prolonged treatment regimen well beyond the period in which there is almost a complete physical recovery of these patients. Also, with a long half-life of seven days, the chances of parasites developing resistance are high. A recent studies showed that after a decade of this drug use in Bihar (India), 6.8 % of patients relapsed within 6 month of treatment [61]. These considerations suggest for alternative strategies to protect this drug from failure due to non-compliance or resistance and to prolong its clinically useful life. One such way is to combine a short course of miltefosine, to which compliance should be high, with a short course of another effective anti-leishmanial compound to obtain complete cure and to protect against single-agent resistance (Table 2).
Sitamaquine
Sitamaquine is another oral drug after miltefosine developed by Walter Reed Army Institute of Research (WRAIR, USA) in collaboration with GlaxoSmithKline (UK). Clinical trials using this drug have been completed in India, Kenya and Brazil [62–65] with cure rate ranging from 27 to 87 %. A major side effect was nephrotoxicity. Exact mechanism of this drug is not known but it is thought that it targets succinate dehydrogenate causing oxidative stress in leishmania parasites [66]. Further development of this molecule has been abandoned.
Pentamidine, an aromatic diamidine that emerged earlier in Bihar, India as a second line drug to circumvent the problems of SbV resistant in VL patients. However, due to inferior cure rate to AmB and toxicity issues (cardiac, hypotension, diabetes mellitus, gastrointestinal), use of this drug as monotherapy has been abandoned in endemic areas [67]. It is commercially available as Pentacarinat® (Sanofi-Aventis). Pentamidine is currently recommended as secondary prophylaxis in HIV-VL co-infection. The mechanism of action of pentamidine in Leishmania and other kinetoplastids is the inhibition of active transport system and DNA-mitochondrial complex [68].
Multidrug therapy
In VL, multidrug therapy has been advocated for several reasons: i) reduce the treatment time and cost; ii) slow the emergence of parasite resistance as mode of action of drugs will be different; iii) increase the efficacy rate even in the case of co-infection [20]. This strategy of multidrug treatment has been successfully used in the treatment of tuberculosis, malaria and leprosy. It also holds promises especially in complicated situations like HIV co-infection. Ideally, drugs used in combination therapy must be of synergistic and additive effect. One of the best approaches is to use one very active drug with a short half-life with second slow acting drug having a longer half-life to clear the remaining parasites. A comparative overview of different combination therapy studies for treatment of VL in India has been presented in Table 4, which suggests that multidrug therapies are safe and effective.
Table 4 Studies on combination therapy for VL in India
Immune responses and immunomodulatory activity of anti-leishmanial drugs
One of the major hurdles for developing an effective vaccine for VL, as well as safer and more appropriate drugs and therapies, has been a limited understanding of the precise immune mechanisms required for controlling parasite growth (reviewed in ref. [69]). It has been thought that clinical efficacy of the disease treatment not only depends on direct effect of drugs alone, but an effective immune response also play critical role in final cure (Table 1). The use of biological molecules or compounds to stimulate or modulate innate and cell mediated immunity in order to achieve the therapeutic goal has been tested in both preclinical and clinical studies in treatment of leishmaniasis (reviewed in ref.[69]). For example, SbV was not able to clear the parasites in T cell deficient BALB/c mice [70] as well as IFNγ and IL-12 gene knockout mice [71, 72]. Treatment with exogenous IL-12 along with SbV resulted in rapid clearance of L.donovani parasites (Table 1). Later on in subsequent separate study, it was reported that treatment with a single-dose anti-IL-10 receptor monoclonal antibody and daily low doses of Sbv dramatically enhance the therapeutic effects of Sbv in experimental mice model [73]. These findings strongly supported the idea that immune mechanisms play an important role in clinical outcome of disease. This was further demonstrated by studies on human VL, where stronger parasitological and clinical cure have been observed with recombinant human IFNγ along with SSG compared with the SSG drug alone from India, Brazil and Kenya [74–76]. Basu et al. reported that SAG induces generation of reactive oxygen species (ROS) and nitric oxide (NO) dependent parasite killing via phosphorylation of ERK1/2 and p38 MAPK [77]. Similar immunomodulatory activity is also reported with miltefosine which induces IFN-γ, TNF-α and IL-12 production from macrophages [78]. In PKDL, miltefosine induces significant increase in levels of pro-inflammatory cytokines with concomitant decrease of anti-inflammatory cytokines via up-regulation of activation markers CD16 and CD 86 and down regulation of CD14 in circulating monocytes [79]. AmB has been shown to induce the production of TNF-α [80], IL-6 [81, 82], IL1ß [83–85] and M-CSF [86] from macrophage and monocytes and simultaneous suppression of mRNA expression of IL-10 and TNF-ß [87]. Therefore, immune based therapies in combination with chemotherapy that enhance immune responses to fight VL are of significant clinical interest. Such novel approaches may be of very useful for therapies to stimulate the immune system where patients are immune-compromised, such as those with HIV-VL co-infection.
Treatment failure and parasite drug resistance
Treatment of VL cases is complicated by patients' late presentation at an advanced stage of their illness; and treatment outcome mainly depends on the interaction between the drug, the parasite and the human host [88]. Treatment failure is well documented for Sbv but the mechanism is far from being completely understood. Most alarming reports came from Bihar (India), where 65 % of VL-patients were found to be unresponsive to Sbv treatment, while in Nepal, recent reports indicate an unresponsiveness rate of up to 24 % in one district [89, 90]. Recently, it was reported that multiple Sbv resistance mechanism are circulating in the Indian subcontinent [91] including the loss of metal reduction, over-expression of thiol metabolism enzymes, multi drug resistant transporter and reduced drug uptake due to decreased expression of aquaporins in different experimental models [92]. However, knowledge gained from transcriptional profiling studies and proteomic approaches emphasized the involvement of HSP's, histones, calpain-related proteins and MAPK [93]. While the metabolomics studies have identified many changes and variation in the lipid composition that alters the membrane fluidity [94] and amino acid composition [95]. These facts suggested for the adaptability of the parasite, and therefore, genome plasticity in Leishmania which has further been validated by Downing and colleagues, to prove the existence of different genetic background in drug resistant parasites within a single geographical area [96] thereby consolidating the idea for the existence of drug resistant phenotypes in the population. Many other reports for the drug resistance have been available attributing to the role of efflux transporters, aquaporins, and alterations in the intracellular thiol levels in drug resistant clinical isolates has been discussed ahead.
AmB resistance, though rare, has been known to result in changes in the sterol profile where the ergosterol is replaced by its precursor cholesta-5,7,24-trien-3-ol in the membrane of parasite thereby reducing its affinity towards the drug. Amplification in the extra chromosomal DNA which has been directly associated with the resistant phenotypes [97]. The mechanism of resistance has further been explored by the proteomic analysis that shed light on the involvement of energetic pathways which are up-regulated including the glycolytic and TCA cycle while documenting the role of reactive oxygen species (ROS) scavenging pathways and heat shock proteins as additional weapon for protection against the drug induced stress [98]. As mentioned above, the role for the efflux pump (MDR) remains to be the important factor driving the drug resistance together with the thiol machinery for better coping up the ROS induced oxidative stress [99].
Emerging resistance against miltefosine is a matter of serious concern as it is the only available oral anti-leishmanial drug. Incomplete treatment and long half-life of this drug in the circulation has been thought to be one of the factors for driving the parasite machinery for adaptability against the drug induced stress. The exact mechanism of which could be imputed to the allele specific mutations in P-glycoprotein-LdRos3 and LdMT [100] which are responsible for drug uptake in ideal conditions, but the mutation causes the gene inactivation and consequently decreasing the drug accumulation and drug translocation in parasite. Apart from above mentioned reasons increased drug efflux has been another threatening cause of drug resistance. Mode of parasite killing involves the induction of apoptosis by accumulation of ROS but the resistant phenotype has been known to alter the cellular machinery and thereby reducing ROS mediated apoptotic phenomenon. The resistant phenotypes have also been known to be armed for coping up the oxidative stress by up-regulating several important enzymes as superoxide dismutase and ascorbate peroxidase [101].
Paromomycin, another drug targeting the parasite mitochondrial protein synthesis machinery has led the parasite to emerge as a strong survivor with reduced drug binding to the surface, increased translational activities with up-regulation of glycolytic enzymes and intracellular proteins, high expression levels of ATP-Binding Cassette (ABC) transporters [51]. The developments in the field of omics technologies like DNA microarray, MALDI, SILAC has further provided newer insight into the underlying mechanisms for the changes in gene copy number either by gene deletion, amplification or gene rearrangements.
Emergence and spreading of drug resistance can dramatically jeopardize the VL control program relying on chemotherapy, as shown in malaria. It is thought that inadequate treatment, either regimen or treatment duration, is the main cause for failure of treatment and resulting in emergence of drug resistance [102]. Nothing is known about the dynamics of drug resistant Leishmania populations in the presence or absence of drug pressure. Therefore, monitoring of drug efficacy and early reporting are essential to bring corrective actions in drug policy. This requires tools, a standardized way to use them and a structure to implement them: in the mid-term, a network of sentinel sites could be established by the VL elimination program, like it was done in East Africa for malaria [103].
What are the possible solutions?
Although considerable scientific progress has been made over the past decade in the broad domain of leishmaniasis, including the genome sequencing of various pathogens causing different form of leishmaniasis, these have not had any impact so far on the quality of clinical care for VL in the field due to very limited number of available anti-leishmanial drugs. It is very important to safeguard the effectiveness of these drugs in order to cure patients and to sustain the VL control. For this, the uninterrupted supply of quality drugs, the promotion of treatment adherence and the monitoring of treatment effectiveness as well as drug resistance will be pivotal. One of the major hurdles for identifying VL patients who are unlikely to respond adequately to chemotherapy, has been a limited understanding of the precise immune mechanisms required for controlling parasite growth, particularly the immune mechanisms that are generated following drug treatment. Anti-leishmanial drugs as monotherapy are high risk of emergence of resistant parasites [16], therefore multidrug therapy needs to be recommended. Another important problem is disease relapse following drug treatment, and at present there are no good prognostic markers to identify individuals that might fail drug treatment. Because the knowledge on mechanisms of emergence of drug resistance, its dynamics and the impact of the introduction of new drugs is poor, and validated methods to monitor treatment of effectiveness under routine conditions do not exist, it is therefore very urgent to develop new tools to allow monitoring treatment effectiveness and drug resistance in order to support the drug policy of the VL elimination program. Furthermore, treatment outcome (the end of treatment) is not definite and patients need to be followed up 6 months after treatment to assess cure. This makes monitoring treatment effectiveness in routine conditions difficult, as patients may not come back for the requested visit 6 months post-treatment. Hence there is a need to compare existing and develop new approaches to monitor treatment effectiveness at the program level. Several possibilities exist: to work with proxy indicators, to develop a method adapted from the retrospective cohort analysis used in TB programs, to give incentives as transport allowances to patients etc.
Importantly, patients with PKDL represent an important but largely neglected reservoir of infection that perpetuates anthroponotic Leishmania donovani disease in India, and focal VL outbreaks have been linked to an index case of PKDL [104]. Treatment of PKDL in India is widely regarded as unsatisfactory, and the low incidence of PKDL in India makes any prospective clinical study challenging. Lack of animal models for PKDL is another challenge for laboratory testing of new drugs. Therefore, more research on an intervention that can reduce the risk of developing PKDL; and characterization of parasite strain are needed to resolve the mystery of this disease.
The use of chemotherapy alone as control tool is limited by the fact that only sick people will be treated. There are asymptomatic carriers of the parasite (estimated 6 times more than VL patients) [105–107], and in the absence of chemoprophylaxis of leishmaniasis, these will obviously not be exposed to the drug [3]. Exact role of asymptomatic infection in disease transmission is unknown, but control programs should take them into consideration, hence role of asymptomatic should be quickly elucidated in context to VL transmission.
Last but not the least, not only VL treatment programs should be maintained and improved, but research should also be taken into consideration those parasite reservoirs in populations in order to reduce the risk of transmission. Programs based on management of vector control should be continued as a critical part of treatment strategy. Research on development of safe and effective vaccine have to be promoted that could make a significant impact on the re-emergence of VL cases and sustain the transmission level in endemic areas.
In the absence of effective vaccine and vector control measures, control of VL and PKDL almost exclusively depends on chemotherapy. The available drugs are costly and may require hospitalization that needs monitoring which cause substantial loss of income for affected families. Emergence of drug resistance further complicates the treatment of disease. Multidrug regimens for VL hold much promise and, experiences with single dose L-AmB are excellent and this will have obvious benefits to the patients who will not require hospital care and loss of wages. However, more studies are required on treatment of PKDL and HIV-VL co-infections as they serve as silent reservoir in endemic areas, and as such will jeopardize the sustainability of VL elimination in the ISC. We have now entered in the VL elimination year, and it is best time to repeat the experience of smallpox and polio eradication in order to open a whole new public health era for next generations.
AmB:
Amphotericin B deoxycholate
cluster of differentiation
ERK:
extra cellular signal regulated kinases
i.v:
intravenously
IL-10:
intramuscularly
ISC:
L-AmB:
Liposomal Amphotericin B
MAPK:
mitogen activated protein kinases
M-CSF:
macrophase colony stimulating factor
MDR:
multi drug resistance
NO:
PKDL:
post kala-azar dermal leishmaniasis
R&D:
ROS:
reactive oxygen species
SSG:
sodium stibogluconate
TCA:
tri cyclic acid cycle
TNF:
VL:
visceral leishmaniasis
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This work was supported by Extramural Programme of the National Institute of Allergy and Infectious Disease (NIAID), National Institute of Health (TMRC Grant No.P50AI074321) and grant from the Bill & Melinda Gates Foundation (OPP 1117011). Om Prakash Singh has received travel support to attend scientific meeting from the Council of Scientific and Industrial Research (CSIR), Delhi; Department of Biotechnology (DBT), Delhi and Immunology Foundation, Delhi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Authors would like to dedicate this article to all those patients who lost their lives during drug trials in various part of the world.
Infectious Disease Research Laboratory, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
Om Prakash Singh, Bhawana Singh, Jaya Chakravarty & Shyam Sundar
Om Prakash Singh
Bhawana Singh
Jaya Chakravarty
Shyam Sundar
Correspondence to Shyam Sundar.
OPS and SS conceived the idea, collected and organized the data of review. OPS, BS, JC and SS critically read, edited and approved the final version of article. No writing assistance was utilized in the production of this manuscript.
Singh, O.P., Singh, B., Chakravarty, J. et al. Current challenges in treatment options for visceral leishmaniasis in India: a public health perspective. Infect Dis Poverty 5, 19 (2016). https://doi.org/10.1186/s40249-016-0112-2


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Q: What happens if there is no exit system call in an assembly program? In an assembly program, the .text section is loaded at 0x08048000; the .data and the .bss section comes after that.
What would happen if I don't put an exit syscall in the .text section? Would it lead to the .data and the .bss section being interpreted as code causing "unpredictable" behavior? When will the program terminate -- probably after every "instruction" is executed?
I can easily write a program without the exit syscall, but testing if .data and .bss gets executed is something I don't know because I guess I would have to know the real machine code that is generated under-the-hoods to understand that.
I think this question is more about "How would OS and CPU handle such a scenario?" than assembly language, but it is still interesting to know for assembly programmers etc.

A: The processor does not know where your code ends.  It faithfully executes one instruction after another until execution is redirected elsewhere (e.g. by a jump, call, interrupt, system call, or similar).
If your code ends without jumping elsewhere, the processor continues executing whatever is in memory after your code.  It is fairly unpredictable what exactly happens, but eventually, your code typically crashes because it tries to execute an invalid instruction or tries to access memory that it is not allowed to access.
If neither happens and no jump occurs, eventually the processor tries to execute unmapped memory or memory that is marked as "not executable" as code, causing a segmentation violation.  On Linux, this raises a SIGSEGV or SIGBUS.  When unhandled, these terminate your process and optionally produce core dumps.
If you're curious, run under a debugger and look at disassembly of the faulting instruction.

redpajama_set_name: RedPajamaStackExchange


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A Pandemic Winner, Walmart Might Be Seeing Cracks in Its Armor
15.02.2021 Market News admin 0
As a provider of vaccines, Walmart could see in-store sales tick up
A TikTok deal may be dead for now, but Walmart's love for the shared-video app is still alive
Walmart's plate is full as it faces minimum wage hikes
Remember the old days, when Walmart's (WMT) earnings were mostly about apparel and food sales and how the world's largest retailer was juggling its tens of thousands of stores to help consumers "Save Money. Live Better."?
When WMT opens its books on Feb. 18, it's likely to include a lot of that—those sales are still the driving forces behind the Bentonville, Arkansas, behemoth's triple-digit billion-dollar revenues every quarter.
But WMT has so much more on its plate that goes beyond how consumers once stood in long lines at the stores to have their baskets of goods rang up. The COVID-19 pandemic helped catapult WMT and its e-commerce site to top of mind for many consumers who might otherwise not have shopped there, and WMT has said it intends to keep those new customers coming and those faithful standbys loyal.
As it continues its battle against Amazon (AMZN) on books, apparel, home goods, and, increasingly, groceries, WMT has been unloading a number of new initiatives that are costing it money while adding perks and other efficiencies. Analysts will probably want to hear how all that is shaking out.
It's also taxed WMT financially as well as operationally and we've seen the mega store make quick technological and logistical adjustments in an effort to smooth out the bumps, step up speed in everything from shelving to home delivery, and convert stores to better meet the omnichannel needs of consumers.
In the time of COVID, it's gone beyond driving traffic to stores through curbside pickup and buy online, pickup in stores to offering vaccinations at its pharmacies. It might be too soon to tell how well that may or may not work out, but analysts might be expecting an early rundown of what WMT is seeing and whether those shots to the arms are also pumping sales at the checkouts.
FIGURE 1: ROLLBACK. In the early days of the pandemic, Walmart (WMT—candlestick) was one of the go-to retailers that thrived while others shifted to lockdown and in some cases "survival" mode. Since then the rest of the S&P Retail Industry ($SPSIRE—purple line) have caught up—and even surpassed—WMT in terms of performance. Data sources: NYSE, S&P Dow Jones Indices. Chart source: The thinkorswim® platform from TD Ameritrade. For illustrative purposes only. Past performance does not guarantee future results.
E-Commerce v. In-Store Sales
WMT's online sales in the last quarter were ablaze, shooting 79% higher on a year-over year basis, accounting for a greater share of the retailer's $134.7 billion in revenue. But its in-store transactions slumped 14%. At the same time, average tickets were 24% higher, suggesting consumers were shopping less often but stocking up when they did.
These are potential signals that consumer spending habits may be changed for good—or for a long, long time—that even WMT Chief Executive Doug McMillon acknowledged on the quarterly conference call.
"There were behavioral changes from shoppers that drove our e-commerce business, and pick-up business," McMillon said at the virtual Consumer Electronics Show in January.
"Many of those things won't go back," he added. "Pick-up and delivery are going to grow and be bigger." It'll be interesting to hear what other steps WMT has taken to keep up with this new trend and the performance of the first few months of Walmart+.
Walmart Earnings and Options Activity
When WMT releases results ahead of the bell Thursday, Feb 18, it's expected to report adjusted earnings of $1.50 per share—up from $1.38 in the prior-year quarter, according to third-party consensus analyst estimates. Revenue is projected at $148.1 billion, up 4.5% from a year ago.
The options market has priced in an expected share price move of 3.8% in either direction around the earnings release.
Looking at the Feb 19 options expiration, put activity has been scattered but higher at the 141 and 143 strikes. Calls have seen more activity, with the highest concentration at the 155 strike. Implied volatility was at the 23rd percentile as of Friday morning.
Note: Call options represent the right, but not the obligation, to buy the underlying security at a predetermined price over a set period of time. Put options represent the right, but not the obligation, to sell the underlying security at a predetermined price over a set period of time.
Is Too Much Now Too Much?
Some analysts fear these operational challenges of meeting shifting consumer demand with delivery, curbside pickup, and buy online, pickup in store, or BOPIS, while also presenting as compelling a shopping experience as possible in a Walmart store might have overloaded the system.
Let's not forget, workers had to quickly adapt to closed stores and an onslaught of online business in Q1 and Q2 that required some folks to take on jobs they had never had before. And WMT had to rush to bring on thousands of workers and train them to handle that initial overflow nearly a year ago.
Not all analysts are down on WMT, but the question of when enough is enough might be a good one for the C-level.
WMT is joining a handful of others ranging from pharmacies to football stadiums opening their doors to vaccine-seeking consumers. While there might not be much to buy at a football stadium, there are plenty of grab-and-go items at WMT stores, which number more than 4,700 in the U.S.
Not all stores will be in the business of jabbing vials into consumer arms, but of those that are, analysts think some spillover spending could happen, tapping into the "since-I'm-out shopping" mode.
Between federally allocated vaccine doses and state supplies, WMT is poking arms in 33 states. Analysts said they want to know what WMT does with extras or leftovers taken out of refrigeration that need to be used when all the reservations have ended. It can be a tricky issue considering all the different mandates of who is eligible at what levels and who isn't from state to state.
And There's TikTok
Let's not forget that quirky social network of short videos that WMT still wants a piece of. For now, however, it's willing to stay an enthusiastic outsider by continuing to promote products on it.
"If you're watching a TikTok video and somebody's got a piece of apparel or an item on it that you really like, what if you could just quickly purchase that item?" McMillon said on CNBC late last year when WMT emerged as a partner buyer with Oracle (ORCL) of the service. "That's what we're seeing happen in countries around the world. And it's intriguing to us, and we would like to be part of it."
You might recall all the ballyhoo about plans to ban TikTok while forcing a sale of video-sharing app to a U.S. based company. ORCL and WMT were two possible buyers, but that's been put on hold for the moment.
It'll be interesting to hear if WMT will touch on this when it opens its books.
And Then Some …
There are a number of issues unrelated to store operations and vaccines WMT is managing that could be brought up during the conference call:
Robotics. WMT has had some mixed results in bringing technology into stores as a means of freeing up workers' duties and augmenting efficiencies for consumers.Double duty for stores. WMT has expanded its test of using back-of-the-store for inventory stocking and online ordering and delivery fulfillment. Minimum wage. There's talk about hiking the minimum wage from $7.25 per hour to $15. Given WMT employs around 1.5 million in the U.S. alone, it'll be interesting to hear comments on this as it could be a significant cost increase.
Good Trading,
@TDAJJKinahan
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redpajama_set_name: RedPajamaCommonCrawl


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Categories: Current Affairs News Commentary Politics
The Truth Before Our Very Eyes?
When it comes to complex situations, it's easy — but often inaccurate — to understand things if they're broken into convenient dichotomies. Russians are all bad, and Ukrainians are all good. Putin is crazy, and Zelensky is a hero. Russian media is pure propaganda, but the Ukrainian media tells the truth.
The manner in which an entire country is being cancelled — some are even giving up cooking Russian food and speaking the language — suggest that that's the case. But what if the truth is somewhere in the middle, as the saying goes?
Controlling the Narrative, from A to 'Z'
As thousands throng the 81,000-seater Luzniki Stadium — one of the biggest stadiums in Europe and Russia's biggest — attendees can be seen waving the Russian tricolour and flags bearing the letter 'Z' in jubilant support of the Russian president and his "special military operation" in Ukraine.
Across Russia, the Z emblem is being used today to signify support for the ongoing Ukraine invasion. It can be found affixed on cars, t-shirts, flags and even on Russian gymnast Ivan Kuliak's outfit as he shared a podium with Ukrainian gold-medalist Illia Kovtun at the Apparatus World Cup in early March. In Kazan, terminally-ill patients in a children's hospice were made to brave the cold and form a 'Z' in support of the war.
While some may be quick to judge that Russians could not possibly be so blind to what's happening, and that their pledge of support for the invasion must be due to coercion, the reality on the ground is different.
According to Radio Free Europe, some 71% of Russians — most are from the older demographic — are proud of the war with Ukraine. "Polls also showed that three-quarters of the Russian population learns news about the war from television. Of these, 87% (and 64% of all Russians) are from state TV channels. 22% of Russians use a radio to get news, and only one percent of respondents have access to information on shortwave," reports the US-government funded organisation.
Besides a growing stranglehold on social media and western websites in recent years, the new 'fake news' law signed by President Putin on 4 March has further consolidated the Kremlin's control on the Ukraine invasion narrative. Source: Statista
This is no fluke. Russia is being led by a former Cold War warrior who's honed his skills to influence and shape worldviews, particularly through the Russian government's strong control over state media, over decades.
He comes from the same KGB that prided itself in being one of the premier intelligence agencies — if not the best — in the world during the Cold War. "Many experts consider the KGB to be the world's most effective information-gathering organisation," wrote John Kohan for TIME in 1983, when Putin was an active-duty KGB officer.
Historians Tom Holland and Dominic Sandbrook describe Putin as a keen student of Lenin and admirer of Stalin, perhaps one of the most effective propagandists in history. Source: Wikipedia Commons
"In the 1930s the KGB was full of thugs. Now it has become an elite that skims the cream from the universities," said Leonard Shapiro, a Soviet specialist at the London School of Economics, to Kohan.
Indeed, this is the route that Putin took as well. The KGB had targeted Putin as a potential recruit even before the young student had graduated with his law degree at Leningrad State University in 1975.
He joined a KGB that was second to none in human intelligence, being able to persuade, entice or entrap thousands to work for them. If anything, his rise from obscurity to the presidency in a short few years hints at his powers of persuasion.
The Second Chechen War of 1999-2000 paved former FSB director Vladimir Putin's path to the presidency of Russia. While the war's brutality and success secured an easy victory for Putin, the suspicious events that preceded the war have called its pretext into question. Source: Wikipedia Commons
He is also known to directly address international audiences through op-eds in the New York Times ostensibly without the assistance of high-priced PR firms. At home, he has created a narrative that the enemy in Ukraine is comprised of neo-Nazis and drug addicts who are oppressing native Russians in the Donbas region.
The only reason why more balanced coverage of the invasion has been possible can be attributed to the presence of large groups of foreign reporters in Ukraine, rather than news outlets relying on their Moscow bureau chiefs for reportage.
To that end, those who have been covering the anti-war protests have been detained by the Russian authorities, and some journalists like AP's video journalist, Mstyslav Chernov, have been hunted for their work. A policeman told him, "If they [Russian forces] catch you, they will get you on camera and they will make you say that everything you filmed is a lie."
It is of little surprise, then, that we are hearing anecdotes of people being unable to persuade family members in Russia that Ukraine is being attacked. The young-old divide is becoming more apparent when older Russians brand their children as traitors for opposing the war in Ukraine.
Media sites in early March reported that social media platforms Facebook and Instagram agreed to loosen hate and violent speech constraints in posts against Russian invaders. Source: Unsplash by Piotr Cichosz
In response, a Lithuanian team launched a project called #CallRussia to galvanise the Russian-speaking diaspora to call Russians, at random, to break through the Russian media's control of the narrative and offer them a different take on the war. The provided script helps Russian speakers navigate the thorny subject, including tips on what to do when the conversation is going the wrong way, or the speaker on the other end claims they are lying.
While the Russian economy has not completely collapsed (yet), Putin is winning the information war at home. But are Russia's accusations completely without merit?
Actors, Nazis and Bears, Oh My!
In a case of art imitating life, we have, on the other side of the ring, one Volodymyr Zelensky, a former actor/comedian who starred in a TV series about a teacher who became the president of Ukraine after his rants about corruption in Ukraine went viral.
His meteoric rise in politics is often attributed to his masterful use of social media during his presidential campaign. It's no wonder, then, that Zelensky also became a popular figure on social media in the opening days of the Russian invasion. Many postings celebrated the affable president and his wife, who were facing such intense circumstances.
If anything, Zelensky has proven he can match Putin in raw persuasion power. From his casual dress sense and effective use of words, he's been able to work press conferences like a seasoned professional and galvanise world opinion to cancel an entire country.
But also lost in the noise was any mention that Zelensky himself has been shown to have offshore holdings in the British Virgin Islands (itself not indicative of corruption), which were conveniently transferred to a friend before he won the presidential vote. This comes on the heels of him having railed Ukrainian oligarchs for this very behaviour during his campaign.
Speaking of oligarchs, the man once known as the boss of the actor-turned-president, billionaire Ihor Kolomoisky, was also a significant presidential campaign contributor and is also accused of money laundering, violence and corruption.
And to what extent has the beleaguered Ukrainian president played his hand under the threat of the Russian bear?
He recently conceded that "it is clear that Ukraine is not a member of NATO; we understand this" despite insisting on NATO membership just a month earlier. Ukraine's membership in NATO was one of the supposed reasons for the Russian invasion, and an earlier concession by Zelensky might have altered the course of the war.
And that's to say nothing of the rest of his administration, media and military. As the information war rages on, Ukrainians have been caught using incorrect, fake or staged media to gain popular worldwide support. These include incorrectly used images of dead toddlers, a misleading video of a brave standoff between a Russian warship and soldiers on Snake Island, and outright propaganda using drone footage from an entirely different event.
But most troubling of all is the involvement of the far-right Azov Batallion in the east. Every profile of the militia on mainstream news channels repeat a familiar motif: They're far-right, ultranationalist and hold to neo-Nazi beliefs.
Depending on who you ask, the battalion has also been linked to rape and torture of detainees in the Donbas region, besides being involved in breaking agreed-upon ceasefires there. But, owing to the lack of long-term, independent investigative journalists in a literal warzone, how much do we know is true?
Alleged members of the battalion have taken to social media to share their war exploits, from 'victory' to 'victory', especially on Telegram. Deutsche Welle describes this problem simply: "[Members of the Azov Battalion] released a picture of a dead man in uniform, purported to be a Russian general whom it had killed. It is difficult to verify these claims."
Amid the chaos and fluid information battlefield, any narrative about the battalion — be it accurate or falsified — can be easily turned into fact, making it easy for Russia to justify its accusations.
What's more sure is that the major powers are still split on how they are addressing the Russian invasion of Ukraine.
A Brief History of Ukraine-Russia Relations
What's an Invasion Between Friends?
The two most populous countries in the world, China and India, have not condemned the Russian invasion of Ukraine. China has described its diplomatic ties with Russia as a "limitless" friendship, whereas India has taken the stance that historical ties with Russia, which came to India's aid in the 1971 war against Pakistan, prevail.
Behind the Great Chinese Firewall, the Xi Jinping government has been effectively controlling the narrative on the invasion. For one, the word "invasion" is often avoided when referring to the conflict, and the government mimics Russian talking points on the casus belli of the war — US and NATO expansionism.
But there have been pockets of dissent. According to the BBC, Douying, China's TikTok equivalent, Weibo, Bilibili and WeChat have all actively removed posts and banned user accounts deemed not to be in lockstep with the central government's narrative.
In a rare rebuke by Chinese scholar Hu Wei, a political scientist from the Counselor's Office of the State Council, he cautions that China should "cut off" their relationship with Putin at the soonest. "China should avoid playing both sides, give up being neutral and choose the global mainstream position… If China plays a part in ending the war — potentially a nuclear war — its tense relations with Western nations will ease and it will be able to emerge from isolation," he stated.
In her recent article for the South China Morning Post, senior correspondent Maria Siow dug into how China and India's refusal to condemn Russia will affect its reputations in ASEAN. Unsurprisingly, Indonesia, which relies on Russia for weaponry, has not condemned Russia, nor have Vietnam and Laos, who have longstanding ideological ties with China.
According to Siow, the diplomatic calculus is that although India is not taking the same side as the world's diplomacies, its reputation in ASEAN will be less affected because it will likely be against China if the latter decides to be aggressive. But when it comes to China, the concern is that the refusal to condemn Russia's actions indicate what it might do to its weaker neighbours — and the ASEAN community will likely take a stronger, united stance against China in that scenario.
Questionable news and social media tactics can do much to degrade people's trust in the news coming out of Ukraine. People naturally feel a deep sense of sadness and concern over images of dead bodies amid the violence and destruction taking place there. It would be a shame if those feelings were betrayed by lies.
As the information war rages on in the coming months, we as media consumers would do well to be more critical of what is being fed to us from all sides — and not jump to conclusions amid the fog of this chaotic mess we call war.
Frank Nelwan
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Often junior high and high school teachers have teenagers with Asperger's Syndrome (AS) included in their classrooms, and are not given much in the way of useful information. Here I hope to provide a few practical tips that may be helpful to educators with no practical knowledge about students on the spectrum.
Parents, you may wish to print this out to give to your child's teacher, or send them the link. There are only a few tips here, but usually teachers are receptive so practical information that may help them to understand and reach their student.
* It's a good idea to have a hard copy of the homework assignment to hand to your students on the spectrum, because most of them are mono-channel, meaning they have only one other processing channels (auditory or visual) working effectively at one time. This means they cannot look at the assignment on the board, write it down and still be able to focus on what you are saying. By the time they have finished copying down the assignment, they have missed your intro to that day's lesson. This mono-channel aspect makes it hard for a student to multi-task, and by only requiring him/her to do one thing at a time, it will be much easier for the student to be focused on the day's lesson.
* This taking things literally means that also the student may not understand all the nuances of language or social customs, what we call 'hidden curriculum.' Think of what it is like as a foreigner in a new land and how they need to be explained the local customs- that is what it is like for a person on the spectrum.
* Students on the spectrum are often described as being obsessed with a particular topic or subject, for example, space travel, buildings, certain types of music, transportation. Actually, being passionate about a topic shows an interest in learning. If you know what your student is passionate about, you can relate your lessons or subject in some way to his area of interest and your student will excel.
* Many students on the spectrum are overly sensitive to noise and crowds, making transition times between classrooms difficult. By allowing the student to arrive or leave a few minutes early or late, you will make it much easier for that student to arrive to class less stressed, and ready to focus on the lesson.
Students with Asperger's Syndrome or HFA are usually very bright and eager to learn. Hopefully these tips will help the year be a more productive one for you and your student.