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Clinical Trial
. 2022 Oct 12;75(8):1423-1432.
doi: 10.1093/cid/ciac127.

AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial

Sakib Burza  1   2 , Raman Mahajan  1 , Shahwar Kazmi  1 , Neal Alexander  2 , Deepak Kumar  1 , Vikash Kumar  1 , Estrella Lasry  1 , Amit Harshana  1 , Alan de Lima Pereira  1 , Pradeep Das  3 , Neena Verma  3 , Vidya Nand Ravi Das  3 , Chandra Shekhar Lal  3 , Bharat Rewari  4 , Vishal Goyal  5 , Suman Rijal  5 , Fabiana Alves  5 , Naresh Gill  6 , Krishna Pandey  3
Affiliations
Clinical Trial

AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial

Sakib Burza et al. Clin Infect Dis. .

Abstract

Background: Visceral leishmaniasis (VL) in patients with human immunodeficiency virus (HIV) presents an increasingly important patient cohort in areas where both infections are endemic. Evidence for treatment is sparce, with no high-quality studies from the Indian subcontinent.

Methods: This is a randomized, open-label, parallel-arm, phase 3 trial conducted within a single hospital in Patna, India. One hundred and fifty patients aged ≥18 years with serologically confirmed HIV and parasitologically confirmed VL were randomly allocated to 1 of 2 treatment arms, either a total 40 mg/kg intravenous liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals) administered in 8 equal doses over 24 days or a total 30 mg/kg intravenous AmBisome administered in 6 equal doses given concomitantly with a total 1.4 g oral miltefosine administered through 2 daily doses of 50 mg over 14 days. The primary outcome was intention-to-treat relapse-free survival at day 210, defined as absence of signs and symptoms of VL or, if symptomatic, negative parasitological investigations.

Results: Among 243 patients assessed for eligibility, 150 were recruited between 2 January 2017 and 5 April 2018, with no loss to follow-up. Relapse-free survival at day 210 was 85% (64/75; 95% CI, 77-100%) in the monotherapy arm, and 96%, (72/75; 90-100%) in the combination arm. Nineteen percent (28/150) were infected with concurrent tuberculosis, divided equally between arms. Excluding those with concurrent tuberculosis, relapse-free survival at day 210 was 90% (55/61; 82-100%) in the monotherapy and 97% (59/61; 91-100%) in the combination therapy arm. Serious adverse events were uncommon and similar in each arm.

Conclusions: Combination therapy appears to be safe, well tolerated, and effective, and halves treatment duration of current recommendations.

Clinical trials registration: Clinical Trial Registry India (CTRI/2015/05/005807; the protocol is available online at https://osf.io/avz7r).

Keywords: HIV; India; liposomal amphotericin B; miltefosine; visceral leishmaniasis.

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Conflict of interest statement

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Trial profile. Abbreviations: D, day; ITT, intention-to-treat; PKDL, post–kala-azar dermal leishmaniasis; VL, visceral leishmaniasis.
Figure 2.
Figure 2.
Kaplan-Meier graphs for mortality. Abbreviations: Amb, AmBisome; Milt, miltefosine.
Figure 3.
Figure 3.
Kaplan-Meier graph for participants without relapse-free survival (ie, treatment failure at day 29, mortality and/or relapse). Abbreviations: Amb, AmBisome; Milt, miltefosine.
Figure 4.
Figure 4.
Box plot graph of study endpoints. A, Including day 210 primary endpoint. B, All day 390 secondary endpoints. Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; TB, tuberculosis; VL, visceral leishmaniasis.
Figure 5.
Figure 5.
A–D, Evolution of CD4 count and HIV viral load over 12 months. CD4 categories: Cat 1 = <50, Cat 2 = 50–99, Cat 3 = 100–199, Cat 4 = 200–349, Cat 5 = ≥350 cells/µL. HIV viral load categories: Cat 1 = <150, undetectable; Cat 2 = 150 to <3 log10; Cat 3 = ≥3 to <4 log10; Cat 4 = ≥4 to <5 log10; Cat 5 = ≥5 to <6 log10; Cat 6 = ≥6 log10 copies/mL. Abbreviations: D, day; HIV, human immunodeficiency virus.
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References

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