Koert Ritmeijer

Liposomal Amphotericin B for the Treatment of Visceral Leishmaniasis

During the past decade, liposomal amphotericin B has been used with increasing frequency to treat visceral leishmaniasis (VL). The World Health Organization convened a workshop to review current knowledge and to develop guidelines for liposomal amphotericin B use for VL. In Europe, liposomal amphotericin B is widely used to treat VL. In Africa and Asia, the VL disease burden is high and drug access is poor; liposomal amphotericin B is available only through preferential pricing for nonprofit groups in East Africa. Clinical trials and experience demonstrate high efficacy and low toxicity for liposomal amphotericin B (total dose, 20 mg/kg) in immunocompetent patients with VL. Combination trials in areas with antileishmanial drug resistance, and treatment and secondary prophylaxis trials in VL-human immunodeficiency virus-coinfected patients, are important to safeguard the current armamentarium and to optimize regimens. The public health community should work to broaden access to preferential liposomal amphotericin B pricing by public sector VL treatment programs.

A Comparison of Miltefosine and Sodium Stibogluconate for Treatment of Visceral Leishmaniasis in an Ethiopian Population with High Prevalence of HIV Infection

BACKGROUND Antimonials are the mainstay of visceral leishmaniasis (VL) treatment in Africa. The increasing incidence of human immunodeficiency virus (HIV) coinfection requires alternative safe and effective drug regimens. Oral miltefosine has been proven to be safe and effective in the treatment of Indian VL but has not been studied in Africa or in persons with HIV and VL coinfection. METHODS We compared the efficacy of miltefosine and sodium stibogluconate (SSG) in the treatment of VL in persons in Ethiopia. A total of 580 men with parasitologically and/or serologically confirmed VL were randomized to receive either oral miltefosine (100 mg per day for 28 days) or intramuscular SSG (20 mg/kg per day for 30 days). RESULTS The initial cure rate was 88% in both treatment groups. Mortality during treatment was 2% in the miltefosine group, compared with 10% in the SSG group. Initial treatment failure was 8% in the miltefosine group, compared with 1% in the SSG group. Among the 375 patients (65%) who agreed to HIV testing, HIV seroprevalence was 29%. Among patients not infected with HIV, initial cure, mortality, and initial treatment failure rates were not significantly different (94% vs. 95%, 1% vs. 3%, and 5% vs. 1% for the miltefosine and SSG groups, respectively). Initial treatment failure with miltefosine occurred in 18% of HIV-coinfected patients, compared with treatment failure in 5% of non-HIV-infected patients. At 6 months after treatment, 174 (60%) of the 290 miltefosine recipients and 189 (65%) of the 290 SSG recipients experienced cure; 30 (10%) of 290 in the miltefosine group and 7 (2%) of 290 in the SSG group experienced relapse, and the mortality rate was 6% in the miltefosine group, compared with 12% in the SSG group. HIV-infected patients had higher rates of relapse (16 [25%] of 63 patients), compared with non-HIV-infected patients (5 [5%] of 131). CONCLUSIONS Treatment with miltefosine is equally effective as standard SSG treatment in non-HIV-infected men with VL. Among HIV-coinfected patients, miltefosine is safer but less effective than SSG.

Conflict and Kala-Azar: Determinants of Adverse Outcomes of Kala-Azar among Patients in Southern Sudan

We analyzed data obtained from 3365 patients with kala-azar (KA) or post-KA dermal leishmaniasis (PKDL) treated by Medecins Sans Frontieres-Holland in south Sudan from October 1998-May 2002. Patients were malnourished (median body mass index [BMI], 15.5; median weight for height [WFH], 75.5%) and anemic (median hemoglobin (Hb) level, 8.5 g/dL). The proportion of patients with primary KA who were children <5 years old increased from 2.5%, in 1998, to 19.8%, in 2002 (P<.0001). Therapy with sodium stibogluconate cured 91.9% of patients with primary KA, and dosages of >850 mg per day did not decrease the chances of survival. Risk factors for death among adults were age > or =45 years (odds ratio [OR], 4.6), malnutrition (BMI, <13; OR, 11.0), anemia (Hb level, <8 g/dL; OR, 4.0), and duration of illness (duration, > or =5 months; OR, 2.3). Risk factors for death among children and adolescents were age <2 years (OR, 5.4,), malnutrition (WFH, <60%; OR, 5.0), anemia (Hb level, <6 g/dL; OR, 3.7), and splenomegaly (OR, 2.9). A higher risk of death was associated with episodes of diarrhea (OR, 1.4), vomiting (OR, 2.7), and bleeding (OR, 2.9). Relapse and PKDL occurred in 3.9% and 10.0% of cases, respectively.

Ethiopian visceral leishmaniasis: generic and proprietary sodium stibogluconate are equivalent; HIV co-infected patients have a poor outcome

We evaluated generic sodium stibogluconate (SSG) (International Dispensary Association, Amsterdam) versus Pentostam (sodium stibogluconate, GlaxoWellcome, London) under field conditions in Ethiopian patients with visceral leishmaniasis (VL; kala-azar). The 199 patients were randomly assigned to Pentostam (n = 104) or SSG (n = 95) in 1998/99; both drugs were given at 20 mg/kg intra-muscularly for 30 days. A clinical cure after 30-days treatment was achieved in 70.2% (Pentostam) and 81.1% (SSG). There were no significant differences between the 2 drugs for the following parameters: frequency of intercurrent events (vomiting, diarrhoea, bleeding or pneumonia) or main outcome (death during treatment and death after 6-month follow-up; relapse or post kala-azar dermal leishmaniasis at 6-months follow-up). Twenty-seven patients had confirmed co-infection with HIV. On admission, HIV co-infected VL patients were clinically indistinguishable from HIV-negative VL patients. The HIV co-infected VL patients had a higher mortality during treatment (33.3% vs 3.6%). At 6-month follow-up, HIV-positive patients had a higher relapse rate (16.7% vs 1.2%), a higher death rate during the follow-up period (14.3% vs 2.4%), and more frequent moderate or severe post kala-azar dermal leishmaniasis (27.3% vs 13.3%). Only 43.5% of the HIV-positive patients were considered cured at 6-months follow-up vs 92.1% of the HIV-negative patients. HIV-positive patients relapsing with VL could become a reservoir of antimonial-resistant Leishmania donovani.

Concordant HIV Infection and Visceral Leishmaniasis in Ethiopia: The Influence of Antiretroviral Treatment and Other Factors on Outcome

BACKGROUND Coinfection with human immunodeficiency virus (HIV) and Leishmania donovani visceral leishmaniasis (VL) in Africa is an emerging, poorly understood disease. METHODS We evaluated 356 consecutive patients coinfected with HIV and VL treated in Humera, northwest Ethiopia, from February 2003 to October 2006, for risk factors for VL relapse and death and the effect of antiretroviral therapy (ART). RESULTS During 2928 patient-months of follow-up, 256 VL episodes and 39 deaths occurred. Among 195 patients receiving ART, 31.3% had > or = 1 VL episode, and 14.4% died. Among 161 patients who did not receive ART, 26.1% had > or = 1 VL episodes, and 6.8% died. A total of 54 patients who received ART and 58 patients who did not receive ART had > or = 1 VL relapse. VL relapse among patients receiving ART was associated with a baseline CD4 cell count < 100 cells/microL (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.21-5.15) and > or = 2 previous VL episodes (HR, 3.74; 95% CI, 1.40-10.02). Failure to clear parasites after VL treatment was usually followed by symptomatic VL relapse. Patients who relapsed showed poor CD4 cell count recovery while receiving ART. ART was partially protective against VL relapse (HR, 0.46; 95% CI, 0.26-0.82). However, 28% of first VL relapses while receiving ART occurred despite a CD4 cell count > 200 cells/microL; in 5% of VL relapses, the CD4 cell count had been > 200 cells/microL for > 6 months. Factors associated with all-cause mortality among patients receiving ART were baseline CD4 cell count < 100 cells/microL (HR, 3.20; 95% CI, 1.30-7.87) and VL episodes during follow-up (HR for 1 episode, 4.97 [95% CI, 2.09-11.86]; HR for > 2 episodes, 3.22 [95% CI, 1.01-10.23]). CONCLUSIONS Concordant HIV infection and VL is a major, acquired immunodeficiency syndrome-defining illness with high relapse and mortality rates; ART reduces relapses; and secondary antileishmanial prophylaxis may benefit patients at risk of relapse.

Developments in the treatment of visceral leishmaniasis

Background: Visceral leishmaniasis (VL) is one of the most neglected parasitic diseases causing large scale mortality and morbidity among the poorest of the poor in the Indian subcontinent and Africa. Objective: This review aims to describe the potential and the (lack of) current impact of newly developed treatments on the control of VL. It describes how the problem of an empty research pipeline is addressed, and discusses the emerging threat of incurable HIV/VL coinfection. Methods: The literature was searched for drugs used in VL. Conclusion: Research and development of VL drugs has received a financial boost but no new drugs are expected in the next 5 years. Only three new and highly effective treatments have been licensed in the past 10 years. These remain, however, largely inaccessible as VL control programs in the developing world are lacking. This is deserving of immediate and urgent attention, especially in the context of the rapidly expanding HIV/VL coinfection.

A randomized comparison of branded sodium stibogluconate and generic sodium stibogluconate for the treatment of visceral leishmaniasis under field conditions in Sudan.

Summary objective  To compare the outcome of treatment of Sudanese kala‐azar patients treated under field conditions with either branded sodium stibogluconate (SSG) (Pentostam GlaxoWellcome) or generic SSG (Albert David Ltd, Calcutta, supplied by International Dispensary Association, Amsterdam).

Evaluation of a mass distribution programme for fine-mesh impregnated bednets against visceral leishmaniasis in eastern Sudan

During an epidemic of visceral leishmaniasis (VL) in eastern Sudan, Médecins Sans Frontières distributed 357 000 insecticide‐treated bednets (ITN) to 155 affected villages between May 1999 and March 2001. To estimate the protective effect of the ITN, we evaluated coverage and use of ITN, and analysed VL incidence by village from March 1996 to June 2002. We provided ITN to 94% of the individuals >5 years old. Two years later, 44% (95% CI 39–48%) of nets were reasonably intact. Because ITN were mainly used as protection against nuisance mosquitoes, bednet use during the VL transmission season ranged from <10% during the hot dry months to 55% during the beginning of the rainy season. ITN were put up from 9 to 11 p.m., leaving children unprotected during a significant period of sandfly‐biting hours after sunset. Regression analysis of incidence data from 114 villages demonstrated a significant reduction of VL by village and month following ITN provision. The greatest effect was 17–20 months post‐intervention, with VL cases reduced by 59% (95% CI: 25–78%). An estimated 1060 VL cases were prevented between June 1999 and January 2001, a mean protective effect of 27%. Although results need to be interpreted with caution, this analysis indicates a potentially strong reduction in VL incidence following a community distribution of ITN. The effectiveness of ITN depends on behavioural factors, which differ between communities.

Comparison of an rK39 dipstick rapid test with direct agglutination test and splenic aspiration for the diagnosis of kala-azar in Sudan

We compared an rK39 dipstick rapid test (Amrad ICT, Australia) with a direct agglutination test (DAT) and splenic aspirate for the diagnosis of kala‐azar in 77 patients. The study was carried out under field conditions in an endemic area of north‐east Sudan. The sensitivity of the rK39 test compared with splenic aspiration was 92% (46/50), the specificity 59% (16/27), and the positive predictive value 81% (46/57). Compared with the diagnostic protocol used by Médecins sans Frontières, the sensitivity of the rK39 test was 93% (50/54), the specificity 70% (16/23), and the positive predictive value 88% (50/57). Compared with splenic aspirates, the sensitivity of a DAT with a titre ≥1:400 was 100% (50/50), but its specificity only 55% (15/27) and the positive predictive value was 80% (50/62). Using a DAT titre ≥1:6400, the sensitivity was 84% (42/50), the specificity 85% (23/27) and the positive predictive value 91% (42/46). All four patients with DAT titre ≥1:6400 but negative splenic aspirate were also rK39 positive; we consider these are probably ‘true’ cases of kala‐azar, i.e. false negative aspirates, rather than false DAT and rK39 seropositives. There were no false negative DATs (DAT titre ≤1:400 and aspirate positive), but there were four false negative rK39 tests (rK39 negative and aspirate positive). The rK39 dipstick is a good screening test for kala‐azar; but further development is required before it can replace the DAT as a diagnostic test in endemic areas of the Sudan.

Limited Effectiveness of High-Dose Liposomal Amphotericin B (AmBisome) for Treatment of Visceral Leishmaniasis in an Ethiopian Population With High HIV Prevalence

BACKGROUND Due to unacceptably high mortality with pentavalent antimonials, Médecins Sans Frontières in 2006 began using liposomal amphotericin B (AmBisome) for visceral leishmaniasis (VL) patients in Ethiopia who were severely ill or positive for human immunodeficiency virus (HIV). METHODS We used clinical data obtained from January 2007 to January 2009 to compare outcomes by HIV status and VL episode (primary vs relapse) and to identify risk factors for treatment failure among patients treated with AmBisome monotherapy at a total dose of 30 mg/kg in 6 doses on alternate days, a higher dose than recommended by the World Health Organization (20 mg/kg). RESULTS Among 94 HIV-negative severely ill VL patients, 93% had initial cure and 6% died. Among 195 HIV-positive patients (116 primary, 79 relapse VL), 60% had initial cure, 7% died, and 32% were parasitological failures. AmBisome was less effective in the 79 HIV-positive VL relapse patients (38% initial cure, 5% mortality, 56% parasitological failure) than in the 116 HIV-positive primary VL patients (74% initial cure, 8% mortality, 16% parasitological failure). Sodium stibogluconate (SSG) rescue treatment increased the overall cure rate among all HIV-positive VL patients from 60% to 83%, but 16% (9 of 59) of rescue treatment patients died, mainly due to SSG toxicity. CONCLUSIONS High-dose AmBisome for VL is safe and effective in severely ill HIV-negative patients, and safe but less effective in HIV-positive patients. Combining AmBisome with another drug may enhance its effectiveness in HIV-positive VL patients. SSG should be avoided for treatment of VL in HIV-positive patients.