Drug resistance in Indian visceral leishmaniasis.
01 Nov 2001-Tropical Medicine & International Health (Trop Med Int Health)-Vol. 6, Iss: 11, pp 849-854
TL;DR: Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first‐line drug instead of Sbv, and the new oral antileishmanial drug miltefosine is likely to be the first-line drug in future.
Abstract: Throughout the world, pentavalent antimonial compounds (Sb(v)) have been the mainstay of antileishmanial therapy for more than 50 years. Sb(v) has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb(v) was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb(v) has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb(v). Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb(v) resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb(v) to reach similarly effectiveness against the parasite as in Sb(v) responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb(v) refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb(v). The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost.
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TL;DR: Research for leishmaniasis has been more and more focusing on the development of new tools such as diagnostic tests, drugs and vaccines, and the newly available control tools should allow a scaling up of control activities in priority areas.
Abstract: Leishmaniasis represents a complex of diseases with an important clinical and epidemiological diversity. Visceral leishmaniasis (VL) is of higher priority than cutaneous leishmaniasis (CL) as it is a fatal disease in the absence of treatment. Anthroponotic VL foci are of special concern as they are at the origin of frequent and deathly epidemics (e.g. Sudan). Leishmaniasis burden remains important: 88 countries, 350 million people at risk, 500,000 new cases of VL per year, 1-1.5 million for CL and DALYs: 2.4 millions. Most of the burden is concentrated on few countries which allows clear geographic priorities. Leishmaniasis is still an important public health problem due to not only environmental risk factors such as massive migrations, urbanisation, deforestation, new irrigation schemes, but also to individual risk factors: HIV, malnutrition, genetic, etc em leader Leishmaniasis is part of those diseases which still requires improved control tools. Consequently WHO/TDR research for leishmaniasis has been more and more focusing on the development of new tools such as diagnostic tests, drugs and vaccines. The ongoing effort has already produced significant results. The newly available control tools should allow a scaling up of control activities in priority areas. In anthroponotic foci, the feasibility of getting a strong impact on mortality, morbidity and transmission, is high.
2,150 citations
TL;DR: Governed by parasite and host factors and immunoinflammatory responses, the clinical spectrum of leishmaniasis encompasses subclinical (inapparent), localised (skin lesions), and disseminated infection (cutaneous, mucosal, or visceral).
1,621 citations
TL;DR: It is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.
Abstract: Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.
1,450 citations
Cites background from "Drug resistance in Indian visceral ..."
...The cash-starved population buys antileishmanial drugs in installments, and most do not complete treatment (141) as disease symptoms are alleviated quickly....
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...However, the region endemic for VL in North Bihar, India, has the unique distinction of being the only region in the world where widespread primary failure to Sb(V) has been reported (141, 144, 154)....
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TL;DR: The immunomodulator imiquimod has proved to be an adjunct for CL therapy and the search for new drugs continues, with bisphosphonates, for example, risedronate and pamidronate, and plant derivatives being reported to have activity against experimental animal infections.
851 citations
TL;DR: Based on the previous experience of 20 years of coinfection in Europe, this review focuses on the management of Leishmania-HIV-coinfected patients in low-income countries where leishmaniasis is endemic.
Abstract: Summary: To date, most Leishmania and human immunodeficiency virus (HIV) coinfection cases reported to WHO come from Southern Europe. Up to the year 2001, nearly 2,000 cases of coinfection were identified, of which 90% were from Spain, Italy, France, and Portugal. However, these figures are misleading because they do not account for the large proportion of cases in many African and Asian countries that are missed due to a lack of diagnostic facilities and poor reporting systems. Most cases of coinfection in the Americas are reported in Brazil, where the incidence of leishmaniasis has spread in recent years due to overlap with major areas of HIV transmission. In some areas of Africa, the number of coinfection cases has increased dramatically due to social phenomena such as mass migration and wars. In northwest Ethiopia, up to 30% of all visceral leishmaniasis patients are also infected with HIV. In Asia, coinfections are increasingly being reported in India, which also has the highest global burden of leishmaniasis and a high rate of resistance to antimonial drugs. Based on the previous experience of 20 years of coinfection in Europe, this review focuses on the management of Leishmania-HIV-coinfected patients in low-income countries where leishmaniasis is endemic.
776 citations
Cites background from "Drug resistance in Indian visceral ..."
...Although the extent of overlap between both infections is still limited, the potential for coinfection in this focus is very high, especially if one considers that these patients are a source of drug resistance due to their unresponsiveness to any antileishmania drug, in an area already threatened by a high rate of resistance to antimonials (251)....
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References
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TL;DR: In India, 320 patients with visceral leishmaniasis received identical pentavalent antimony (Sb) treatment, and Sb induced long-term cure in 35% of those in Bihar versus 86% (95% CI, 79%-93%) of Those in Uttar Pradesh.
Abstract: In India, 320 patients with visceral leishmaniasis (209 in the state of Bihar and 11 in the neighboring state of Uttar Pradesh) received identical pentavalent antimony (Sb) treatment. Sb induced long-term cure in 35% (95% confidence interval [CI], 28%-42%) of those in Bihar versus 86% (95% CI, 79%-93%) of those in Uttar Pradesh. In Bihar, the center of the Indian epidemic, traditional Sb treatment should be abandoned.
606 citations
"Drug resistance in Indian visceral ..." refers background in this paper
...More than 100 000 cases of VL occur in India alone every year, and state of Bihar accounts for more than 90% of these (Bora 1999; Sundar et al. 2000a,b)....
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...In most of the studies (Sundar et al. 1998b, 2000b; Jha et al. 1999) at this dose, >95% of patients were cured consistently....
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...%) relapsed (Sundar et al. 2000a)....
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...Special amphotericin B treatment centres with trained personnel need to established in these areas; on the other hand continued use of Sbv, although convenient, cheaper and easily applicable, is associated with high incidence of cardiotoxicity and deaths (Sundar et al. 1997a, 1998a, 2000a)....
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TL;DR: Orally administered miltefosine appears to be an effective treatment for Indian visceral leishmaniasis.
Abstract: Background There is no effective orally administered medication for any leishmania infection. We investigated miltefosine, which can be taken orally, for the treatment of Indian visceral leishmaniasis. Miltefosine is a phosphocholine analogue that affects cell-signaling pathways and membrane synthesis. Methods The study was an open-label, multicenter, phase 2 trial in which four 30-person cohorts received 50, 100, or 150 mg of miltefosine per day for four or six weeks. The 120 patients, who ranged in age from 12 to 50 years, had anorexia, fever, and splenomegaly with at least moderate (2+) leishmania in a splenic aspirate. A parasitologic cure was defined by the absence of parasites in a splenic aspirate obtained two weeks after completion of treatment. The clinical response was assessed at six months. Results In all 120 patients there was an initial parasitologic cure. Six patients had clinical and parasitologic relapses; the remaining 114 patients had not relapsed by six months after treatment, for a cu...
442 citations
"Drug resistance in Indian visceral ..." refers background in this paper
...In most of the studies (Sundar et al. 1998b, 2000b; Jha et al. 1999) at this dose, >95% of patients were cured consistently....
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TL;DR: A strong correlation (P<.001) between clinical response and SAG sensitivity in vitro was observed only when strains were assayed as intracellular amastigotes, and the emergence of antimony-resistant L. donovani strains appears to be a cause of treatment failures in India.
Abstract: The possibility that the high frequency of treatment failures in Indian kala-azar might be due to infection with antimony-resistant strains of Leishmania donovani has not been experimentally addressed. L. donovani isolates were obtained from splenic aspiration smears of 24 patients in Bihar, India, who either did not respond (15) or did respond (9) to 1 or more full courses of treatment with sodium antimony gluconate (SAG). A strong correlation (P<.001) between clinical response and SAG sensitivity in vitro was observed only when strains were assayed as intracellular amastigotes: responsive isolates ED50=2.4+/-2.6, ED90=6.4+/-7.8 microgram SAG/mL; unresponsive isolates ED50=7.4+/-3.7 microgram SAG/mL, ED90=29.1+/-11.1 SAG/mL. No correlation with clinical response was found by use of extracellular promastigotes (ED50=48+/-22 vs. 52+/-29 microgram/mL). The emergence of antimony-resistant L. donovani strains appears to be a cause of treatment failures in India.
370 citations
"Drug resistance in Indian visceral ..." refers background in this paper
...Thus, the amastigotes from the unresponsive strains were several times more resistant to killing by Sbv than the sensitive ones, and this difference was highly signi®cant (Lira et al. 1999)....
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...Thus, the amastigotes from the unresponsive strains were several times more resistant to killing by Sb than the sensitive ones, and this difference was highly signi®cant (Lira et al. 1999)....
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Journal Article•
TL;DR: Until a safe and effective vaccine is developed, a combination of sandfly control, detection and treatment of patients and prevention of drug resistance is the best approach for controlling kala-azar.
Abstract: Kala-azar has re-emerged from near eradication. The annual estimate for the incidence and prevalence of kala-azar cases worldwide is 0.5 million and 2.5 million, respectively. Of these, 90% of the confirmed cases occur in India, Nepal, Bangladesh and Sudan. In India, it is a serious problem in Bihar, West Bengal and eastern Uttar Pradesh where there is under-reporting of kala-azar and post kala-azar dermal leishmaniasis in women and children 0-9 years of age. Untreated cases of kala-azar are associated with up to 90% mortality, which with treatment reduces to 15% and is 3.4% even in specialized hospitals. It is also associated with up to 20% subclinical infection. Spraying of DDT helped control kala-azar; however, there are reports of the vector Phlebotomus argentipes developing resistance. Also lymphadenopathy, a major presenting feature in India raises the possibility of a new vector or a variant of the disease. The widespread co-existence of malaria and kala-azar in Bihar may lead to a difficulty in diagnosis and inappropriate treatment. In addition, reports of the organism developing resistance to sodium antimony gluconate--the main drug for treatment--would make its eradication difficult. Clinical trials in India have reported encouraging results with amphotericin B (recommended as a third-line drug by the National Malaria Eradication Programme). Phase III Trials with a first-generation vaccine (killed Leishmania organism mixed with a low concentration of BCG as an adjuvant) have also yielded promising results. Preliminary studies using autoclaved Leishmania major mixed with BCG have been successful in preventing infection with Leishmania donovani. Until a safe and effective vaccine is developed, a combination of sandfly control, detection and treatment of patients and prevention of drug resistance is the best approach for controlling kala-azar.
251 citations
"Drug resistance in Indian visceral ..." refers background in this paper
...More than 100 000 cases of VL occur in India alone every year, and state of Bihar accounts for more than 90% of these (Bora 1999; Sundar et al. 2000a,b)....
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TL;DR: Treatment with miltefosine at 100-150 mg/day for 4 weeks has promise as an effective oral treatment of visceral leishmaniasis including antimony-resistant infection.
233 citations
"Drug resistance in Indian visceral ..." refers background in this paper
...There are several manufacturers of Sbv in India, and not all produce consistent quality products, resulting in occasional batches being substandard and toxic, and adding to the problems associated with Sbv therapy and serious toxicity and deaths related to the drug (Sundar et al. 1998a)....
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...In most of the studies (Sundar et al. 1998b, 2000b; Jha et al. 1999) at this dose, >95% of patients were cured consistently....
[...]
...Special amphotericin B treatment centres with trained personnel need to established in these areas; on the other hand continued use of Sbv, although convenient, cheaper and easily applicable, is associated with high incidence of cardiotoxicity and deaths (Sundar et al. 1997a, 1998a, 2000a)....
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