Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial

Iroh Tam, Pui-Ying ORCID: https://orcid.org/0000-0002-3682-8892, Arnold, SLM, Barrett, LK, Chen, cr, Conrad, TM, Douglas, E, Gordon, MA, Herbert, D, Henrion, Marc, Herman, D, Hollingsworth, B, Houpt, E, Jere, KC, Lindblad, R, Love, MS, Makhaza, L, McNamara, CW, Nedi, W, Nyirenda, J, Operario, DJ, Phulusa, J, Quinnan, GV, Sawyer, LA, Thole, H and TotoMtunthama, Neema (2021) 'Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial'. Clinical Infectious Diseases, Vol 73, Issue 2, pp. 183-191.

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Abstract

Background: We evaluated efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in HIV-infected patients with cryptosporidiosis.
Methods: We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in Part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched HIV-infected individuals without cryptosporidiosis.
Results: Twenty Part A and 10 Part B participants completed the study ATP. Almost all Part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the Part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared to the placebo group. Over the inpatient period, compared to those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit: 3.82), total stool weight decreased by 45.3 g (p=0.37), and number of diarrheal episodes increased by 2.32 (p=0.87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. Three CFZ and 1 placebo subjects died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than Part B controls.
Conclusion: Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy.

Item Type:	Article
Subjects:	QV Pharmacology > Drug Standardization. Pharmacognosy. Medicinal Plants > QV 771 Standardization and evaluation of drugs QX Parasitology > QX 4 General works WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503 Acquired immunodeficiency syndrome. HIV infections WC Communicable Diseases > Tropical and Parasitic Diseases > WC 730 Coccidiosis
Faculty: Department:	Clinical Sciences & International Health > Malawi-Liverpool-Wellcome Programme (MLW)
Digital Object Identifer (DOI):	https://doi.org/10.1093/cid/ciaa421
Depositing User:	Marie Hatton
Date Deposited:	15 Apr 2020 10:35
Last Modified:	22 Jul 2021 13:59
URI:	https://archive.lstmed.ac.uk/id/eprint/14075

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