Hot Topics in Infectious Diseases Giuseppe Nunnari

Sakib Burza et al CID 2015 October

Visceral Leishmaniasis Neglected tropical Disease Fatal if untreated Incidence between 146,00-282,800 cases/year 50% occur in India 90% of these in Bihar Relapses occur generally within the first year Relapses are more frequent in HIV+ patients

Estimated to new cases of VL worldwide a year. Over 90% of new cases occur in 6 countries: Bangladesh, Brazil, Ethiopia, India, South Sudan and Sudan.

DEATH RATE 3 TIMES HIGHER WITH ANTIMONY AntimonyAmbisome

Infectious Diseases Society of America IDSA Practice Guidelines

Amphotericin B, miltefosine and paromomycin have been approved for the treatment of visceral leishmaniasis; Miltefosine at a dose of : aged 2–11 years 2.5 mg/kg per day for 28 days to children aged 12 years and above < 25 Kg body weight 50 mg/day for for 28 days 25–50 kg body weight 100 mg/day for for 28 days  50 kg body weight 150 mg/day for for 28 days  has shown a cure rate in immunocompetents of 94% in India (A) and about 90% in Ethiopia (A).

Lipid formulations of amphotericin B: The total dose requirements for treatment of visceral leishmaniasis vary by region. In India (L. donovani) a total dose of > 10 mg/kg results in a cure rate of > 95% (A). In India, a 90% cure rate was found with a single dose of 5 mg/kg, and a 98% cure rate with a single dose of 10 mg/kg (A). Europe and Mediterranean region 3–4 mg/kg per day to a total dose of 15–24 mg/kg, had 90–98% efficacy in southern Europe (B) (L. infantum) It is the reference treatment for visceral leishmaniasis in clinical practice A 96% cure rate was achieved with a total dose of 20 mg/kg administered in two doses (B). East Africa There is limited experience, lower (< 90%) cure rates at a total dose of 20 mg/kg (B), a total dose of 30 mg/kg given in 6–10 doses is now in limited use. studies are under way to determine the minimum effective total dose.

HIV VL co-infection: Lipid formulations infused at a dose of 3–5 mg/kg daily or intermittently for 10 doses (days 1–5, 10, 17, 24, 31 and 38) up to a total dose of 40 mg/kg are recommended (A) Maintenance therapy is limited to patients coinfected with L. infantum in the Mediterranean area. An amphotericin B lipid complex (3–5 mg/kg per dose once) given every 3 weeks for 12 months as secondary prophylaxis was well tolerated: after 1 year, only 22% of patients had relapsed, in comparison with 50% of patients without secondary prophylaxis (A). Other options are: liposomal amphotericin B (3–5 mg/kg per dose once every 3–4 weeks) (C); pentavalent antimonials (20 mg Sb5+/kg per dose once every 3–4 weeks) (C) pentamidine (4 mg/kg per dose once [300 mg for an adult] every 3–4 weeks) (C). Once a patient’s immune function has recovered with antiretroviral treatment and visceral leishmaniasis is quiescent, prophylaxis could be suspended, provided that the CD4+ cell count is maintained at > 200 cells/μl for more than 6 months (B). HOWEVER, the efficacy and required dosage of several of these medicines have not been demonstrated in all endemic areas and may differ between these areas

Liposomal amphotericin B Is FDA-approved for treatment of visceral leishmaniasis Immunocompetent patients 3 mg per kg daily, by IV infusion, on days 1–5, 14, and 21 (total dose of 21 mg/kg). Immunosuppressed patients 4 mg per kg daily on days 1–5, 10, 17, 24, 31, and 38 (total dose of 40 mg/kg). HIV-coinfected patients with CD4 counts <200 cells/mm 3. higher total doses and/or secondary prophylaxis (chronic maintenance therapy), in particular,

In March 2014, FDA approved the oral agent miltefosine for treatment of cutaneous, mucosal, and visceral leishmaniasis caused by Leishmania donovani 30 to 44 kg:one 50-mg oral capsule of miltefosine twice a day (total of 100 mg per day) for 28 consecutive days. >45 kg: 50-mg three times a day (total of 150 mg per day) for 28 consecutive days. Miltefosine is contraindicated in pregnant and breastfeeding women. Off Label Use visceral leishmaniasis caused by other species (e.g., L. infantum) children less than 12 years of age Miltefosine However, standard approaches to: antileishmanial treatment secondary prophylaxis HAVE NOT BEEN ESTABLISHED for example: the optimal agent dose dosing interval for maintenance therapy.

Active follow up 984 patients Healthy MONTHSN°PTSRELAPSE RATE %

Treated patients 8749 Cure Rate 99.3% 8692 Fatality rate: HIV POSITIVE 2.5% HIV NEGATIVE 0.3% Risk of mortality HIV+ 7.9 times higher 20mg/Kg in 4 doses (over 4-10days)

Antimicrob Agents Chemother. 2014;58(1):414-8.

Mortality risk 6 months 14.3% 2 years 22.4% 4 years 29.7% Relapses 1 year 16.1% 2 years 20.4% 4 years 25.9% Mortality Risk factors Low hemoglobin level Concurrent tuberculosis ART initiated shortly after the admission 65% Reduced risk of mortality 75% reduced risk of relapses Ambisome First episode 20mg/kg 4 doses (4-10 days) Relapse 25mg/Kg 4 doses (4-10 days)

Predictors of VL relapse Previous VL relapse Lack of secondary prophylaxis CD4<100 cells at primary VL No increase in CD4 cells ART? Secondary Prophylaxis

Ambisome 30mg/kg in 6 doses on alternate days

HIV – Leishmania Coinfection Higher Relapse Rate Higher Mortality Combination therapy? Miltefosine?

MILTEFOSINE

Miltefosine Failure

99%

Retrospective analysis on 105 patients with HIV+ and VL Ambisome and Miltefosine 14 days Ambisome 30mg/Kg divided in 6 doses/14days, alternate days Miltefosine >25kg-50mg BID/<25kg50mg daily Follow up every month visit during ART collection

Primary endpoint: relapse-free survival during 11 months of follow up – Cumulative incidence of mortality – Cumulative index of poor outcome – Poor outcome= relapse or death

Patients baseline data Median CD4 count 169 (IQR ) 67% had CD4< patients did not receive ART, 4 died 51% already on ART 49% started ART after treatment for VL Primary VL episode 46.1% First or more relapses 54%

Treatment outcome Therapy was well tolerated Minor adverse events for 7 patients – 5 pts nausea and vomiting – 1 back pain – 1 had rigors

16 patients died (15,7%) during follow up Median time to death was 3.3 months 2 patients died before completion of therapy complications related to HIV 4 patients died during the first 2 months 1 died of sepsis for scrotal abscess 1 died from bacterial meningitis

Cumulative incidence of mortality was: 6 months 11.7% 12 months 14. 5% 18 months 16.6%

Relapses Median time to relapse was 11 months (IQR:4-15) 6 months 2.5% 12 months 6.0% 18 months 13.9%

Cumulative index of poor outcome 6 months 13.9% 12 months 18.4% 18 months 27.2%

Relapses %Cumulative index of Mortality % Cumulative Index of poor outcome % 6 months2.5%11.7%13.9% 12 months6.0%14. 5%18.4% 18 months13.9%16.6%27.2% Study Outcome

Predictors of poor outcome Tuberculosis Failure to start ART Already on ART was protective

GOOD First study with combination therapy Well-tolerated BAD Retrospective study No randomization 67% of pts with CD4 <200 Previous relapses 54% All-cause mortality was used Relapse and death equal to earlier studies

Further studies needed Randomized clinical trial – First VL episode – Relapses

Clinical trial Drugs for Neglected Disease Initiative. A randomized trial of AmBisome® monotherapy and combination of AmBisome® and miltefosine for the treatment of VL in HIV positive patients in Ethiopia followed by secondary VL prophylactic treatment with pentamidine. Available at: fieldresearch.msf.org/msf/bitstream/10144/332058/1/1a- DNDiProtocol HIVVLFINALVersion pdf. Accessed 9 July 2015 Vaccine?