Robert Davidson

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

BACKGROUNDnAntimonials 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.nnnMETHODSnWe 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).nnnRESULTSnThe 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).nnnCONCLUSIONSnTreatment 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.

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.

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

Summary objectiveu2002u2002To 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 357u2003000 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 >5u2003years 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 17–20u2003months 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.

Comparison of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis in Kenya

OBJECTIVEnTo compare the use of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis (kala-azar).nnnMETHODSnA total of 102 patients with confirmed kala-azar were treated in a mission hospital in West Pokot region, Kenya, with sodium stibogluconate (20 mg/kg/day for 30 days)--either as Pentostam (PSM) or generic sodium stibogluconate (SSG); 51 patients were allocated alternately to each treatment group.nnnFINDINGSnThere were no significant differences in baseline demographic characteristics or disease severity, or in events during treatment. There were 3 deaths in the PSM group and 1 in the SSG group; 2 patients defaulted in each group. Only 1 out of 80 test-of-cure splenic aspirates was positive for Leishmania spp.; this patient was in the SSG group. Follow-up after > or = 6 months showed that 6 out of 58 patients had relapsed, 5 in the SSG group and 1 in the PSM group. No outcome variable was significantly different between the two groups.nnnCONCLUSIONnThe availability of cheaper generic sodium stibogluconate, subject to rigid quality controls, now makes it possible for the health authorities in kala-azar endemic areas to provide treatment to many more patients in Africa.

Emergence or re-emergence of visceral leishmaniasis in areas of Somalia, northeastern Kenya, and south-eastern Ethiopia in 2000–2001

Visceral leishmaniasis (VL) was known to be endemic in Somalia along the basins of the (Middle) Shebelle and (Lower) Juba rivers, and in Kenya in parts of the Rift Valley, on the border with Uganda and the Eastern Provinces. From May 2000 to August 2001, we diagnosed 904 patients with VL. The patients came from an area which spanned the Wajir and Mandera districts of north-eastern Kenya, southern Somalia, and south-eastern Ethiopia. Small numbers of patients were also seen in northern Somalia. These areas were either previously non-endemic for VL, or had only sporadic cases prior to the epidemic. We describe the features of the outbreak and review the history of VL in the region. Unusual rainfall patterns, malnutrition, and migration of a Leishmania-infected population seeking food and security may have contributed to this outbreak.

Médecins Sans Frontières interventions against kala-azar in the Sudan, 1989–2003

Since 1989, Médecins Sans Frontières (MSF) has provided medical humanitarian assistance during outbreaks of visceral leishmaniasis (VL; kala-azar) in Sudan. First, in western Upper Nile in southern Sudan, where a VL epidemic occurred after the resumption of the civil war in Sudan in 1983, with an estimated 100,000 deaths. Later, MSF started interventions in eastern Upper Nile and Gedaref State. In these two endemic regions VL incidence has risen markedly since 2001, which could be the start of a new epidemic cycle. Outbreaks of VL in Sudan remain unpredictable, and access to affected populations in war-torn southern Sudan is often hampered by insecurity. Therefore, MSF takes a flexible approach, establishing treatment centres where patients can be accessed. From 1989 to 2002, MSF treated >51,000 VL cases in Sudan. Despite very basic field conditions, high cure rates of 95% are being achieved. Lack of diagnostics is a major obstacle to treatment, especially during epidemic situations. Therefore, development of simple and rapid technologies is required, allowing reliable diagnosis under field conditions. For treatment of VL there is a limited choice of effective, affordable drugs. There are strong indications of an emerging resistance to antimonials in Malakal. Introduction of combination therapies is urgently needed to prevent the further emergence and spread of resistance to antimonials, which are still the mainstay of VL treatment in eastern Africa. Experience with combination therapy with sodium stibogluconate (SSG) and paromomycin is promising, and combinations of SSg with liposomal amphotericin B and miltefosine are currently being explored.