Combination Treatment for Visceral Leishmaniasis Patients Coinfected with Human Immunodeficiency Virus in India.

BACKGROUND: There are considerable numbers of patients coinfected with human immunodeficiency virus (HIV) and visceral leishmaniasis (VL) in the VL-endemic areas of Bihar, India. These patients are at higher risk of relapse and death, but there are still no evidence-based guidelines on how to treat them. In this study, we report on treatment outcomes of coinfected patients up to 18 months following treatment with a combination regimen. METHODS: This retrospective analysis included all patients with confirmed HIV-VL coinfection receiving combination treatment for VL at a Médecins Sans Frontières treatment center between July 2012 and September 2014. Patients were treated with 30 mg/kg body weight intravenous liposomal amphotericin B (AmBisome) divided as 6 equal dose infusions combined with 14 days of 100 mg/day oral miltefosine (Impavido). All patients were encouraged to start or continue on antiretroviral therapy (ART). RESULTS: 102 patients (76% males, 57% with known HIV infection, 54% with a prior episode of VL) were followed-up for a median of 11 months (interquartile range: 4-18). Cumulative incidence of all-cause mortality and VL relapse at 6, 12, and 18 months was 11.7%, 14.5%, 16.6% and 2.5%, 6.0%,13.9%, respectively. Cumulative incidence of poor outcome at 6, 12, and 18 months was 13.9%, 18.4%, and 27.2%, respectively. Not initiating ART and concurrent tuberculosis were independent risk factors for mortality, whereas no factors were associated with relapse. CONCLUSIONS: In this Bihar-based study, combination therapy appeared to be well tolerated, safe, and effective and may be considered as an option for treatment of VL in HIV coinfected patients.

Visceral leishmaniasis and HIV co-infection in Bihar, India: long-term effectiveness and treatment outcomes with liposomal amphotericin B (AmBisome).

BACKGROUND: Visceral Leishmaniasis (VL; also known as kala-azar) is an ultimately fatal disease endemic in the Indian state of Bihar, while HIV/AIDS is an emerging disease in this region. A 2011 observational cohort study conducted in Bihar involving 55 VL/HIV co-infected patients treated with 20-25 mg/kg intravenous liposomal amphotericin B (AmBisome) estimated an 85.5% probability of survival and a 26.5% probability of VL relapse within 2 years. Here we report the long-term field outcomes of a larger cohort of co-infected patients treated with this regimen between 2007 and 2012. METHODS AND PRINCIPAL FINDINGS: Intravenous AmBisome (20-25 mg/kg) was administered to 159 VL/HIV co-infected patients (both primary infections and relapses) in four or five doses of 5 mg/kg over 4-10 days. Initial cure of VL at discharge was defined as improved symptoms, cessation of fever, improvement of appetite and recession of spleen enlargement. Test of cure was not routinely performed. Antiretroviral treatment (ART) was initiated in 23 (14.5%), 39 (24.5%) and 61 (38.4%) before, during and after admission respectively. Initial cure was achieved in all discharged patients. A total of 36 patients died during follow-up, including six who died shortly after admission. Death occurred at a median of 11 weeks (IQR 4-51) after starting VL treatment. Estimated mortality risk was 14.3% at six months, 22.4% at two years and 29.7% at four years after treatment. Among the 153 patients discharged from the hospital, 26 cases of VL relapse were diagnosed during follow-up, occurring at a median of 10 months (IQR 7-14) after discharge. After accounting for competing risks, the estimated risk of relapse was 16.1% at one year, 20.4% at two years and 25.9% at four years. Low hemoglobin level and concurrent infection with tuberculosis were independent risk factors for mortality, while ART initiated shortly after admission for VL treatment was associated with a 64-66% reduced risk of mortality and 75% reduced risk of relapse. SIGNIFICANCE: This is the largest cohort of HIV-VL co-infected patients reported from the Indian subcontinent. Even after initial cure following treatment with AmBisome, these patients appear to have much higher rates of VL relapse and mortality than patients not known to be HIV-positive, although relapse rates appear to stabilize after 2 years. These results extend the earlier findings that co-infected patients are at increased risk of death and require a multidisciplinary approach for long-term management.

HIV and visceral leishmaniasis coinfection in Bihar, India: an underrecognized and underdiagnosed threat against elimination.

Although human immunodeficiency virus (HIV) and visceral leishmaniasis coinfection is recognized as a major public health challenge in Africa, data regarding the prevalence in India are very limited. Consecutive HIV screening of 2077 patients aged ≥14 years with confirmed visceral leishmaniasis in Bihar, eastern India, found that 5.6% were HIV positive, including 2.4% with newly diagnosed HIV infection.

Risk factors for visceral leishmaniasis relapse in immunocompetent patients following treatment with 20 mg/kg liposomal amphotericin B (Ambisome) in Bihar, India.

BACKGROUND: A proportion of all immunocompetent patients treated for visceral leishmaniasis (VL) are known to relapse; however, the risk factors for relapse are not well understood. With the support of the Rajendra Memorial Research Institute (RMRI), Médecins Sans Frontières (MSF) implemented a program in Bihar, India, using intravenous liposomal amphotericin B (Ambisome) as a first-line treatment for VL. The aim of this study was to identify risk factors for VL relapse by examining the characteristics of immunocompetent patients who relapsed following this regimen. METHODS AND PRINCIPAL FINDINGS: This is an observational retrospective cohort study of all VL patients treated by the MSF program from July 2007 to August 2012. Intravenous Ambisome was administered to 8749 patients with VL in four doses of 5 mg/kg (for a total dose of 20 mg/kg) over 4-10 days, depending on the severity of disease. Out of 8588 patients not known to be HIV-positive, 8537 (99.4%) were discharged as initial cures, 24 (0.3%) defaulted, and 27 (0.3%) died during or immediately after treatment. In total, 1.4% (n = 119) of the initial cured patients re-attended the programme with parasitologically confirmed VL relapse, with a median time to relapse of 10.1 months. Male sex, age <5 years and ≥45 years, a decrease in spleen size at time of discharge of ≤0.5 cm/day, and a shorter duration of symptoms prior to seeking treatment were significantly associated with relapse. Spleen size at admission, hemoglobin level, nutritional status, and previous history of relapse were not associated with relapse. CONCLUSIONS: This is the largest cohort of VL patients treated with Ambisome worldwide. The risk factors for relapse included male sex, age <5 and ≥45 years, a smaller decrease in splenomegaly at discharge, and a shorter duration of symptoms prior to seeking treatment. The majority of relapses in this cohort occurred 6-12 months following treatment, suggesting that a 1-year follow-up is appropriate in future studies.

Five-year field results and long-term effectiveness of 20 mg/kg liposomal amphotericin B (Ambisome) for visceral leishmaniasis in Bihar, India.

BACKGROUND: Visceral Leishmaniasis (VL; also known as Kala-azar) is an ultimately fatal disease endemic in Bihar. A 2007 observational cohort study in Bihar of 251 patients with VL treated with 20 mg/Kg intravenous liposomal amphotericin B (Ambisome) demonstrated a 98% cure rate at 6-months. Between July 2007 and August 2012, Médecins Sans Frontières (MSF) and the Rajendra Memorial Research Institute (RMRI) implemented a VL treatment project in Bihar, India-an area highly endemic for Leishmania donovani-using this regimen as first-line treatment. METHODS AND PRINCIPAL FINDINGS: Intravenous Ambisome 20 mg/kg was administered in four doses of 5 mg/kg over 4-10 days, depending on the severity of disease. Initial clinical cure at discharge was defined as improved symptoms, cessation of fever, and recession of spleen enlargement. This observational retrospective cohort study describes 8749 patients with laboratory-confirmed primary VL treated over a 5-year period: 1396 at primary healthcare centers, 7189 at hospital, and 164 at treatment camps. Initial clinical cure was achieved in 99.3% of patients (8692/8749); 0.3% of patients (26/8749) defaulted from treatment and 0.4% (31/8749) died. Overall, 1.8% of patients (161/8749) were co-infected with HIV and 0.6% (51/8749) with tuberculosis. Treatment was discontinued because of severe allergic reactions in 0.1% of patients (7/8749). Overall, 27 patients (0.3%) were readmitted with post Kala-azar dermal leishmaniasis (PKDL). Risk factors for late presentation included female sex, age >15 years and being from a scheduled caste. In 2012, a long-term efficacy survey in the same area of Bihar determined relapse rates of VL after 5 years' intervention with Ambisome. Of 984 immunocompetent patients discharged between September 2010 and December 2011, 827 (84.0%) were traced in order to determine their long-term outcomes. Of these, 20 patients (2.4%) had relapsed or received further treatment for VL. Of those completing 6, 12, and 15 month follow-up, 0.3% (2/767), 3.7% (14/383), and 2.4% (4/164), respectively, had relapsed. The mean ±SD time-to-relapse was 9.6±3.0 months. SIGNIFICANCE: This is the largest cohort of VL patients treated with 20 mg/kg Ambisome worldwide. The drug has high initial and long-term efficacy, and a low rate of adverse reactions when administered under field conditions in Bihar, India. Although challenging, its use as first line treatment in rural settings in Bihar is safe and feasible.

Post Kala-Azar dermal leishmaniasis following treatment with 20 mg/kg liposomal amphotericin B (Ambisome) for primary visceral leishmaniasis in Bihar, India.

BACKGROUND: The skin disorder Post Kala-Azar Dermal Leishmaniasis (PKDL) occurs in up to 10% of patients treated for visceral leishmaniasis (VL) in India. The pathogenesis of PKDL is not yet fully understood. Cases have been reported in India following therapy with most available treatments, but rarely in those treated with liposomal amphotericin B (Ambisome). Between July 2007 and August 2012 with the support of the Rajendra Memorial Research Institute (RMRI), Médecins Sans Frontières (MSF) supported a VL treatment programme in Bihar, India-an area highly endemic for Leishmania donovani-in which 8749 patients received 20 mg/kg intravenous Ambisome as first-line treatment. This study describes the characteristics of patients who returned to the MSF supported treatment programme with PKDL. METHODS AND PRINCIPAL FINDINGS: Over a 5-year period, Ambisome was administered to 8749 patients with laboratory-confirmed VL (clinical signs, rK39 positive, with/without parasite confirmation) in four intravenous doses of 5 mg/kg to a total of 20 mg/kg, with a high initial-cure rate (99.3%) and low default rate (0.3%). All patients received health education highlighting the possibility and symptoms of developing PKDL, and advice to return to the MSF programme if these symptoms developed. This is an observational retrospective cohort study of the programme outcomes. Of the 8311 patients completing treatment for their first episode of VL, 24 (0.3%) returned passively to the programme complaining of symptoms subsequently confirmed as PKDL, diagnosed from clinical history, appearance consistent with PKDL, and slit-skin smear examination. Of the 24 patients, 89% had macular lesions, with a median time (interquartile range) to development of 1.2 (0.8-2.2) years following treatment. Comparison of the demographic and clinical characteristics of the VL patients treated with Ambisome who later developed PKDL, with those of the remaining cohort did not identify any significant risk factors for PKDL. However, the time to developing PKDL was significantly shorter with Ambisome than in a subset of patients presenting to the programme with PKDL following previous sodium stibogluconate treatment for VL. CONCLUSIONS: In this large cohort of patients with VL in Bihar who were treated with 20 mg/kg Ambisome, PKDL following treatment appears to be infrequent with no predictive risk factors. The shorter median time to developing symptoms of PKDL compared with that after conventional VL treatments should be taken into account when counseling patients treated with regimens including Ambisome.

Liposomal amphotericin B for visceral leishmaniasis in human immunodeficiency virus-coinfected patients: 2-year treatment outcomes in Bihar, India.

BACKGROUND: Reports on treatment outcomes of visceral leishmaniasis (VL)-human immunodeficiency virus (HIV) coinfection in India are lacking. To our knowledge, none have studied the efficacy of liposomal amphotericin B in VL-HIV coinfection. We report the 2-year treatment outcomes of VL-HIV-coinfected patients treated with liposomal amphotericin B followed by combination antiretroviral treatment (cART) in Bihar, India. METHODS: The study included all patients with newly diagnosed VL-HIV coinfection and initiating treatment with liposomal amphotericin B (20-25 mg/kg in 4-15 days) between July 2007 and September 2010. Kaplan-Meier estimates of the cumulative incidence of death/treatment failure were calculated. RESULTS: Fifty-five patients were included (83.6% male; median age, 35 years; 62% migrant laborers; median follow-up, 1 year). The median CD4 cell count at VL diagnosis was 66 cells/µL (interquartile range, 38-112). Twenty-seven patients (49.1%) presented with VL relapse of VL. The overall tolerance of liposomal amphotericin B was excellent, with no interrupted treatment. Survival by 1 and 2 years after VL treatment was estimated at 85.5%. No patients had initial treatment failure. The probabilities of VL relapse were 0%, 8.1%, and 26.5% at 0.5, 1, and 2 years after VL treatment, respectively; relapse rates were similar for primary VL and VL relapse. CD4 counts <200 cells/µL at 6 months after cART initiation were predictive of subsequent relapse. The mean CD4 cell counts at 6 and 24 months after cART initiation were 187 and 261 cells/µL, respectively. The rate for retention in HIV care was 83.6%. CONCLUSIONS: Good long-term survival and retention rates were obtained for VL-HIV-coinfected patients treated with liposomal amphotericin B and cART. Although the initial VL treatment response was excellent, VL relapse within 2 years remained frequent.

Effectiveness and safety of liposomal amphotericin B for visceral leishmaniasis under routine program conditions in Bihar, India.

We evaluated, through the prospective monitoring of 251 patients at Sadar Hospital in Bihar, India, the effectiveness and safety of 20 mg/kg body weight of liposomal amphotericin B for the treatment of visceral leishmaniasis. The treatment success rates for the intention-to-treat, per protocol, and intention-to-treat worse-case scenario analyses were 98.8%, 99.6%, and 81.3%, respectively. Nearly one-half of patients experienced mild adverse events, but only 1% developed serious but non-life-threatening lips swelling. The lost to follow-up rate was 17.5%. Our findings indicate that the 20 mg/kg body weight treatment dosage is effective and safe under routine program conditions. Given that the exorbitant cost of liposomal amphotericin B is a barrier to its widespread use, we recommend further study to monitor and evaluate a lowered dosage and a shorter treatment course.

Impact of amphotericin-B in the treatment of kala-azar on the incidence of PKDL in Bihar, India.

BACKGROUND & OBJECTIVE: Of the two reservoirs of infection of kala-azar i.e., patients of kala-azar and post kala-azar dermal leishmaniasis (PKDL), PKDL provides easy access for the sandfly to pick up the parasites. In the last epidemic of 1977 in India, the importance of PKDL as a potential cause of increase in number of kala-azar cases was ignored. During recent years, we found an increase in the cases of kalaazar whereas cases of PKDL were decreasing in Bihar. We undertook this study to find out reasons for this phenomenon. METHODS: These three different settings were selected to study the trends of the disease. (i) Cases of PKDL registered in the Dermatology Department of Patna Medical College Hospital (PMCH), one of the largest and oldest teaching hospital in Bihar, between 1970 and 2005; (ii) Rajendra Memorial Research Institute of Medical Sciences, Patna (RMRIMS), a research institute exclusively devoted to kala-azar (2000 and 2005); and (iii) interviews with two leading dermatologists of Patna selected by lottery on the incidence of PKDL and possible causes of its decrease, if any. The number of cases of kala-azar (visceral leishmaniasis, VL) from Bihar was studied from Malaria Departments of the Government of Bihar and Government of India, the two nodal departments dealing with the kala-azar. RESULTS: Analysis of data from Dermatology Department of PMCH showed increase in number of cases of PKDL from two in 1970 to 12 in 1976, a year before the first epidemic of kala-azar in 1977 with 100,000 cases. Kala-azar cases decreased to 11,120 in 1982 due to control measures taken between 1977- 1979 but cases of PKDL reached 28 and kept on increasing. During 1950 to 1977, low dose and short duration regimen of sodium antimony gluconate (SAG) was mainly used in the treatment of kala-azar. Between 1977-1991 increasing incidence of unresponsiveness to SAG, led to the usage of longer duration and higher dose regimen of SAG, more use of amphotericin B (AMB) for SAG resistant cases and also as a first line drug for kala-azar and PKDL. The number of kala-azar cases started decreasing after control measures taken during 1992-1994 but cases of PKDL continued decreasing. The effect of control measures on the incidence of kala-azar was visible upto 2002, but decrease in number of PKDL cases continued. In 2005 the number of PKDL cases was 14 but number of kala-azar cases reached 21,177 in Bihar. In the interview, the two dermatologists also opined that PKDL was decreasing due to increased use of amphotericin B in the treatment of kala-azar. Trend analysis done on the data of PMCH and RMRIMS showed that PKDL will decrease in coming years and kala-azar will increase. INTERPRETATION & CONCLUSION: Incidence of PKDL decreased in PMCH and RMRIMS and also suggested by two dermatologists that extensive use of amphotericin B in the treatment of kala-azar might be responsible for decrease in number of cases of PKDL.