Jaya Chakravarty

Single-Dose Liposomal Amphotericin B for Visceral Leishmaniasis in India

BACKGROUND Some 50% of patients with visceral leishmaniasis (kala-azar) worldwide live in the Indian state of Bihar. Liposomal amphotericin B is an effective treatment when administered in short courses. We wanted to determine whether the efficacy of a single infusion of liposomal amphotericin B was inferior to conventional parenteral therapy, consisting of 15 alternate-day infusions of amphotericin B deoxycholate. METHODS In this open-label study, we randomly assigned 412 patients in a 3:1 ratio to receive either liposomal amphotericin B (liposomal-therapy group) or amphotericin B deoxycholate (conventional-therapy group). Liposomal amphotericin B (at a dose of 10 mg per kilogram of body weight) was given once, and patients were discharged home 24 hours later. Amphotericin B deoxycholate, which was administered in 15 infusions of 1 mg per kilogram, was given every other day during a 29-day hospitalization. We determined the cure rate 6 months after treatment. RESULTS A total of 410 patients--304 of 304 patients (100%) in the liposomal-therapy group and 106 of 108 patients (98%) in the conventional-therapy group--had apparent cure responses at day 30. Cure rates at 6 months were similar in the two groups: 95.7% (95% confidence interval [CI], 93.4 to 97.9) in the liposomal-therapy group and 96.3% (95% CI, 92.6 to 99.9) in the conventional-therapy group. Adverse events in the liposomal-therapy group were infusion-related fever or rigors (in 40%) and increased anemia or thrombocytopenia (in 2%); such events in the conventional-therapy group were fever or rigors (in 64%), increased anemia (in 19%), and hypokalemia (in 2%). Nephrotoxicity or hepatotoxicity developed in no more than 1% of patients in each group. CONCLUSIONS A single infusion of liposomal amphotericin B was not inferior to and was less expensive than conventional therapy with amphotericin B deoxycholate. (ClinicalTrials.gov number, NCT00628719.)

Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial

BACKGROUND Improved treatment approaches are needed for visceral leishmaniasis. We assessed the efficacy and safety of three potential short-course combination treatments compared with the standard monotherapy in India. METHODS Standard treatment (1 mg/kg amphotericin B infusion on alternate days for 30 days, total dose 15 mg/kg) was compared with three drug combinations (single injection of 5 mg/kg liposomal amphotericin B and 7-day 50 mg oral miltefosine or single 10-day 11 mg/kg intramuscular paromomycin; or 10 days each of miltefosine and paromomycin) in an open-label, parallel-group, non-inferiority, randomised controlled trial in two hospital sites in Bihar, India. Patients aged 5-60 years with parasitologically confirmed visceral leishmaniasis were randomly assigned one of the four treatments by the trial statistician by use of a computer-generated list. Clinical assessments were done at the end of treatment (15 days on combination treatment; 31 days for standard treatment) and after 45 days and 6 months. The primary endpoint was definitive cure (defined as no sign or symptom of visceral leishmaniasis and parasitologically cured to the last follow-up). Analyses were done both by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00696969. FINDINGS Between June, 2008, and July, 2009, 634 patients were assigned amphotericin B (n=157), liposomal amphotericin B with miltefosine (n=160) or paromomycin (n=158), or miltefosine and paromomycin (n=159). 618 patients were in the per-protocol population. There were two relapses in each group. The numbers with definitive cure at 6 months for the intention-to-treat population were 146 (cure rate 93·0%; CI 87·5-96·3) for amphotericin B, 156 (97·5%; 93·3-99·2) for liposomal amphotericin B and miltefosine, 154 (97·5%; 93·24-99·2) for liposomal amphotericin B and paromomycin, and 157 (98·7%; 95·1-99·8) for miltefosine and paromomycin. All combinations were non-inferior to the standard treatment, in both the intention-to-treat and per-protocol populations. Patients in the combination groups had fewer adverse events than did those assigned standard treatment. INTERPRETATION Combination treatments for visceral leishmaniasis are efficacious and safe, and decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites. FUNDING Drugs for Neglected Diseases initiative and the Indian Council of Medical Research.

Efficacy of Miltefosine in the Treatment of Visceral Leishmaniasis in India After a Decade of Use

BACKGROUND Miltefosine is the only oral drug available for treatment of Indian visceral leishmaniasis (VL), which was shown to have an efficacy of 94% in a phase III trial in the Indian subcontinent. Its unrestricted use has raised concern about its continued effectiveness. This study evaluates the efficacy and safety of miltefosine for the treatment of VL after a decade of use in India. METHODS An open-label, noncomparative study was performed in which 567 patients received oral miltefosine (50 mg for patients weighing <25 kg, 100 mg in divided doses for those weighing ≥25 kg, and 2.5 mg per kg for those aged <12 years, daily for 28 days) in a directly observed manner. Patients were followed up for 6 months to see the response to therapy. RESULTS At the end of treatment the initial cure rate was 97.5% (intention to treat), and 6 months after the end of treatment the final cure rate was 90.3%. The overall death rate was 0.9% (5 of 567), and 2 deaths were related to drug toxicity. Gastrointestinal intolerance was frequent (64.5%). The drug was interrupted in 9 patients (1.5%) because of drug-associated adverse events. CONCLUSIONS As compared to the phase III trial that led to registration of the drug a decade ago, there is a substantial increase in the failure rate of oral miltefosine for treatment of VL in India.

Leishmaniasis: an update of current pharmacotherapy.

Introduction: Leishmaniasis broadly manifests as visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). The treatment of VL is challenging. The duration of treatment is long, and drugs are toxic thereby needing monitoring and hospitalization. Areas covered: Novel therapies such as single dose of liposomal amphotericin B (L-AmB) and multidrug therapy are important breakthrough for VL in the Indian subcontinent and have been recommended as the treatment of choice in this region. African Leishmania donovani is less susceptible to L-AmB, miltefosine and paromomycin as compared to the Indian strains, and the treatment of choice remains a 17-day combination therapy of pentavalent antimonials (SBv) and paromomycin. L-AmB at a total dose of 18 – 21 mg/kg is the recommended regimen in the Mediterranean region and South America. It is also the treatment of choice for HIV–VL coinfection. Treatment of CL should be decided by the clinical lesions, etiological species and its potential to develop into mucosal leishmaniasis. A literature search on treatment of leishmaniasis was done on PubMed and through Google. Expert opinion: There is an urgent need for exploratory studies with short course, highly efficient regimens such as single dose L-AmB or combination therapy for all the endemic regions of VL. Shorter and more acceptable regimens are needed for the treatment of post–kala-azar dermal leishmaniasis. Treatment of CL remains one of the neglected areas of leishmaniasis as data are scarce and drawn from uncontrolled studies.

New Treatment Approach in Indian Visceral Leishmaniasis: Single-Dose Liposomal Amphotericin B Followed by Short-Course Oral Miltefosine

BACKGROUND In Bihar, India, home to nearly one-half of the worlds burden of visceral leishmaniasis, drug resistance has ended the usefulness of pentavalent antimony, which is the traditional first-line treatment. Although monotherapy with other agents is available, the use of 2 drugs with different modes of action might increase efficacy, shorten treatment duration, enhance compliance, and/or reduce the risk of parasite resistance. To test the feasibility of a new approach to combination therapy in visceral leishmaniasis (also known a kala-azar), we treated Indian patients with a single infusion of liposomal amphotericin B (L-AmB), followed 1 day later by short-course oral miltefosine. METHODS We used a randomized, noncomparative, group-sequential, triangular design and assigned 181 subjects to treatment with 5 mg/kg of L-AmB alone (group A; 45 subjects), 5 mg/kg of L-AmB followed by miltefosine for 10 days (group B; 46 subjects) or 14 days (group C; 45 subjects), or 3.75 mg/kg of L-AmB followed by miltefosine for 14 days (group D; 45 subjects). When it became apparent that all regimens were effective, 45 additional, nonrandomized patients were assigned to receive 5 mg/kg of L-AmB followed by miltefosine for 7 days (group E). RESULTS Each regimen was satisfactorily tolerated, and all 226 subjects showed initial apparent cure responses. Nine months after treatment, final cure rates were similar: group A, 91% (95% confidence interval [CI], 78%-97%]; group B, 98% (95% CI, 87%-100%); group C, 96% (95% CI, 84%-99%]; group D, 96% (95% CI, 84%-99%); and group E, 98% (95% CI, 87%-100%). CONCLUSIONS These results suggest that treatment with single-dose L-AmB followed by 7-14 days of miltefosine is active against Indian kala-azar. This short-course, sequential regimen warrants additional testing in India and in those regions of endemicity where visceral leishmaniasis may be more difficult to treat. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00370825 .

Drug resistance in leishmaniasis

The treatment options of leishmaniasis are limited and far from satisfactory. For more than 60 years, treatment of leishmaniasis has centered around pentavalent antimonials (Sbv). Widespread misuse has led to the emergence of Sbv resistance in the hyperendemic areas of North Bihar. Other antileishmanials could also face the same fate, especially in the anthroponotic cycle. The HIV/ visceral leishmaniasis (VL) coinfected patients are another potential source for the emergence of drug resistance. At present no molecular markers of resistance are available and the only reliable method for monitoring resistance of isolates is the technically demanding in vitro amastigote-macrophage model. As the armametrium of drugs for leishmaniasis is limited, it is important that effective monitoring of drug use and response should be done to prevent the spread of resistance. Regimens of simultaneous or sequential combinations should be seriously considered to limit the emergence of resistance.

A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1 + MPL-SE vaccine for use in the prevention of visceral leishmaniasis

Healthy Indian adult volunteers, with or without a history of leishmaniasis, were evaluated for evidence of previous infection with Leishmania donovani based on the direct agglutination test (DAT). Three cohorts of 6 DAT-negative and 6 DAT-positive subjects were enrolled in an open-label, dose-escalating, uncontrolled clinical trial and received three injections of the LEISH-F1+MPL-SE vaccine (consisting of 5μg, 10μg, or 20μg recombinant Leishmania polyprotein LEISH-F1 antigen+25μg MPL®-SE adjuvant). The study injections were given subcutaneously on days 0, 28, and 56, and the subjects were followed through day 168 for safety and immunological endpoints. The vaccine was safe and well-tolerated in DAT-negative and DAT-positive subjects and induced T-cell production of IFN-γ and other cytokines in response to stimulation with the LEISH-F1 antigen. This clinical trial shows that the LEISH-F1+MPL-SE vaccine is safe and immunogenic in healthy subjects with and without history of previous infection with Leishmania donovani.

Rapid, Noninvasive Diagnosis of Visceral Leishmaniasis in India: Comparison of Two Immunochromatographic Strip Tests for Detection of Anti-K39 Antibody

ABSTRACT Used with blood or serum, a new anti-K39 antibody immunochromatographic strip test (IT-Leish; DiaMed AG) proved sensitive (range, 99 to 100%) and specific (range, 95 to 100%) for the noninvasive serodiagnosis of visceral leishmaniasis in India. Used with serum, the IT-Leish test and the existing Kalazar Detect test (InBios International, Inc.) yielded comparable results for symptomatic infection and identified apparent subclinical infection in 15 to 32% of healthy residents in a region where visceral leishmaniasis is highly endemic.

An update on pharmacotherapy for leishmaniasis.

Introduction: Leishmaniasis broadly manifests as visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis. The treatment of leishmaniasis is challenging and the armamentarium of drugs is small, duration of treatment is long, and most drugs are toxic. Areas covered: A literature search on treatment of leishmaniasis was done on PubMed. Single dose of liposomal amphotericin B (L-AmB) and multidrug therapy (L-AmB + miltefosine, L-AmB + paromomycin (PM), or miltefosine + PM) are the treatment of choice for VL in the Indian subcontinent. A 17-day combination therapy of pentavalent antimonials (Sbv) and PM remains the treatment of choice for East African VL. L-AmB at a total dose of 18 – 21 mg/kg is the recommended regimen for VL in the Mediterranean region and South America. Treatment of CL should be decided by the severity of clinical lesions, etiological species and its potential to develop into mucosal leishmaniasis. Expert opinion: There is an urgent need to implement a single-dose L-AmB or combination therapy in the Indian subcontinent. Shorter and more acceptable regimens are needed for the treatment of post – kala-azar dermal leishmaniasis. Combination therapy with newer drugs needs to be tested in Africa. Due to the toxicity of systemic therapy, a trend toward local treatment for New World CL is preferred in patients without risk of mucosal disease.

Amphotericin B Treatment for Indian Visceral Leishmaniasis: Response to 15 Daily versus Alternate-Day Infusions

BACKGROUND For patients with Indian visceral leishmaniasis, amphotericin B deoxycholate is usually given as 15 alternate-day infusions of 1 mg/kg over 30 days (total dose, 15 mg/kg); daily treatment with 1 mg/kg for 20 days (total dose, 20 mg/kg) is also used. This study was done to address the unsettled therapeutic questions of administration schedule (alternate-day vs. daily administration) and dose (1 vs. 0.75 mg/kg) and to determine whether the duration of amphotericin B treatment in Bihar, India, can be shortened to 15 days. METHODS To compare alternate-day versus daily administration and 1-mg/kg versus 0.75-mg/kg doses and to determine whether the duration of treatment could be abbreviated, Indian subjects randomly received 15 infusions of 1 mg/kg (group A; 245 patients) or 0.75 mg/kg (group B; 244 patients) on alternate days or 1 mg/kg (group C; 500 patients) or 0.75 mg/kg (group D; 496 patients) daily. Noninferiority testing compared 6-month cure rates using a 5% margin. RESULTS Overall, 1439 of the 1485 subjects completed treatment and responded. Treatment interruptions (nephrotoxicity) but not infusion-associated reactions or study removals were more common with daily administration. Final cure rates at 6 months were similar: group A, 234 patients (96%; 95% confidence interval [CI], 92%-98%); group B, 225 patients (92%; 95% CI, 88%-95%); group C, 483 patients (97%; 95% CI, 95%-98%); and group D, 476 patients (96%; 95% CI, 94%-97%; P>.05). CONCLUSIONS Provided that the serum creatinine level is repeated once, daily treatment with amphotericin B, 0.75 mg/kg for 15 days (total dose, 11.25 mg/kg), is efficient and effective for visceral leishmaniasis in India. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00310505.