Directly acting antivirals and Visceral Leishmaniasis: A case report

PRESENTED BY:
VISHNU.R.NAIR,
PHARM-D INTERN,
NATIONAL COLLEGE OF PHARMACY(NCP).

TITLE Direct-acting antivirals and visceral leishmaniasis: a
case report
AUTHORS Claudia Colombia et al.
CASE REPORT SITE Sicily, Italy
JOURNAL INVOLVED BMC Infectious Diseases(Springer)
CONFLICT OF INTERESTS None
DATE OF PUBLICATION 18.04.2019

 Visceral leishmaniasis(VL)  refers to a vector-associated parasitic disease
 Caused by protozoa, belonging to the genus “Leishmania”
 Clinical presentation  influenced by “host immunocompetency”
 Patients may be asymptomatic to severe forms, characterized by fever,
splenomegaly and pancytopenia!
 In immunodeficient conditions (HIV, cirrhosis, immunosuppressive therapies) 
immune system is unable to resolve leishmania infections  allows reactivation
from sites of parasite latency(latent infection)
 Interferon associated VL during chronic hepatitis treatment has been reported
 Effect of direct-acting antivirals (DAA) on other infection reactivation is not well-
documented!
1. Saporito L, Giammanco GM, De Grazia S, et al. Visceral leishmaniasis: hostparasite interactions and clinical presentation in the immunocompetent and in the immunocompromised host. Int J
Infect Dis. 2013;17:572–6.
2. Cascio A, Antinori S, Ricciardi F, Costantino G, Iaria C. Visceral leishmaniasis during pegylated interferon therapy for chronic hepatitis C: first report. Antivir Ther. 2005;10:695–6.

 A Sicilian 70 year old man
Admitted to Infectious Disease Unit of a hospital at Italy in July 2017
With complaints of
Progressive asthenia & irregular fever(refractory to antibiotics), for 2 months
 Past medical history: DM, Mild kidney disease and HCV-related liver cirrhosis
 Medication history: Sofosbuvir & ledipasvir (for past 24 weeks) [for HCV
infection]
Colomba C, Saporito L, Di Carlo P, Tolomeo M, Cervo A, Firenze A, Trizzino M, Cascio A. Direct-acting antivirals and visceral leishmaniasis: a case report. BMC infectious diseases. 2019
Dec;19(1):328.

 3 months, post HCV treatment
Patient suffered from worsening of thrombocytopenia & refractory to steroid
therapy
Treated with romiplostim(when his platelet count was under 20,000/mmc).
Dec;19(1):328.

TEMPERATURE 37.3 degrees
PULSE 78 bpm
B.P Normal
RR Normal
PHYSICAL EXAMINATION Asthenia, hepatosplenomegaly, grade-1
encephalopathy
Colomba C, Saporito L, Di Carlo P, Tolomeo M, Cervo A, Firenze A, Trizzino M, Cascio A. Direct-acting antivirals and visceral leishmaniasis: a case report. BMC infectious diseases. 2019 Dec;19(1):328.

Lab reports:
- Pancytopenia (WBC: 3,100/mmc, neutrophils 46%, lymphocytes
33%, Hb 8.1 g/dl, platelets 46,000/mmc)
- Increased CRP (33 mg/l)
- INR: 1.5
- Estimated GFR: 63 ml/min/BSA
- AST/ALT: 2 * ULN
- Modest hypoalbuminemia
Dec;19(1):328.

Other tests:
- Abdominal ultrasound: Increased splenomegaly
- Thoracic CT-Scan: Normal
- Trans-thoracic echocardiography: No vegetations found
- HIV-Ag, HBs-Ag : Negative
- Leishmania serology : Positive in ELISA, immunofluorescent
antibody test & Western Blot
- PCR: Detected Leishmania infantum DNA
- Bone marrow aspirate  not performed, owing to low platelet count.
Dec;19(1):328.

 Final diagnosis was centered at DAA-induced visceral leishmaniasis
 Liposomal Amphotericin-B
Given at dose of 3 mg/kg (for day 1-5)
Further dose on day 10
Total dose: 18 mg/kg.
 Blood cells count, along with clinical manifestations improved
 Treatment was continued, until PCR-test was found negative.
Dec;19(1):328.

 T-cell dependent immune response + macrophage activation
Result in a cascade of events, that trigger Leishmania infection
 Reactivation of latent infection  also associated with immune status
 Although DAA regimens are more effective and safe for HCV as compared to
ribavirin and interferons  high rates of HCC(Hepatocellular carcinoma) are now
observed in patients with DAA-therapy, as compared to IF-treatment protocols
 DAA  blocks inflammation, secondary to chronic HCV infection  abolishes this
protective & antineoplastic effect
 According to Meissner et al  sofosbuvir & ribavirin  downregulate type II &
III IFNs, their receptors & genes in liver
1. Grandhe S, Frenette CT. Occurrence and recurrence of hepatocellular carcinoma after successful direct-acting antiviral therapy for patients with chronic hepatitis C virus infection. Gastroenterol
Hepatol (N Y). 2017;13:421–5.
2. Meissner EG, Wu D, Osinusi A, et al. Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome. J Clin Invest. 2014;124:3352–63.

Downregulation of type II & III IFNs in liver  produces negative
impact on immune control  allows reactivation of previous infection!
Since HBV reactivation occurs in patients with either chronic HBV /
HCV infections, receiving DAA therapy  it is important to monitor
evidence for concomitant HBV infection & get it managed timely!
Mücke M, Backus LI, Mücke VT, et al. Hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and metaanalysis. Lancet Gastroenterol Hepatol.
2018;3:172–80.

IFN-ϒ  enhances killing mechanisms in macrophages (primary
target sites for Leishmania as well as M.tuberculosis)
DAA therapy  increases potentiality for reactivation of Leishmania
or M.tuberculosis infection!
Health care professionals  should be aware of the potential risk of
unmasking of Leishmania infection due to DAA therapy
Although DAA therapy is not contraindicated in previous Leishmania
infection  routine baseline screening of the same is recommended in
a healthcare setting!

Directly acting antivirals and Visceral Leishmaniasis: A case report

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