Long-term Clinical Outcomes in Visceral Leishmaniasis/Human Immunodeficiency Virus-Coinfected Patients During and After Pentamidine Secondary Prophylaxis in Ethiopia: A Single-Arm Clinical Trial

Ermias Diro, Koert Ritmeijer, Marleen Boelaert, Fabiana Alves, Rezika Mohammed, Charles Abongomera, Raffaella Ravinetto, Maaike De Crop, Helina Fikre, Cherinet Adera, Harry van Loen, Achilleas Tsoumanis, Wim Adriaensen, Asrat Hailu, Johan van Griensven, Ermias Diro, Koert Ritmeijer, Marleen Boelaert, Fabiana Alves, Rezika Mohammed, Charles Abongomera, Raffaella Ravinetto, Maaike De Crop, Helina Fikre, Cherinet Adera, Harry van Loen, Achilleas Tsoumanis, Wim Adriaensen, Asrat Hailu, Johan van Griensven

Abstract

Background: We have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian human immunodeficiency virus-infected patients. Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety. However, remaining relapse-free after PSP discontinuation is vital. We now report outcomes and associated factors for a period of up to 2.5 years after initiating PSP, including 1-year follow-up after PSP discontinuation.

Methods: The trial had 3 phases: (1) 12 months of PSP; (2) a 6-month PSP extension period if CD4 count was ≤200 cells/μL at month 12; and (3) 12-month follow-up after stopping PSP. The probability of relapse and risk factors were calculated using Kaplan-Meier methods and Cox regression analysis.

Results: For the 74 patients included, final study outcomes were as follows: 39 (53%) relapse-free, 20 (27%) relapsed, 5 (7%) deaths, 10 (14%) lost to follow-up. The 2-year risk of relapse was 36.9% (95% confidence interval, 23.4%-55.0%) and was highest for those with a history of VL relapse and low baseline CD4 count. Forty-five patients were relapse-free and in follow-up at month 12 of PSP. This included 28 patients with month 12 CD4 counts >200 cells/µL, remaining relapse-free after PSP discontinuation. Among the 17 with month 12 CD4 count <200 cells/µL, 1 relapsed and 3 were lost during the PSP extension period. During 1-year post-PSP follow-up, 2 patients relapsed and 1 was lost to follow-up. No PSP-related serious adverse events were reported during the PSP-extension/post-PSP follow-up period.

Conclusions: It seems safe to discontinue PSP at month 12 CD4 counts of >200 cells/µL. The management of those failing to reach this level remains to be defined.

Clinical trials registration: NCT01360762.

Keywords: Ethiopia; HIV; pentamidine; secondary prophylaxis; visceral leishmaniasis.

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Flowchart showing the recruitment process and patient outcomes in the pentamidine secondary prophylaxis trial to prevent visceral leishmaniasis (VL) relapse in Ethiopian VL/human immunodeficiency virus–coinfected patients, 2011–2015 (N = 74). The trial had 3 periods: the main treatment period (12 months), a 6-month treatment extension period for those failing to achieve a CD4 count >200 cells/µL by 12 months, and a 1-year posttreatment period. Abbreviations: FU, follow-up; HIV, human immunodeficiency virus; LTFU, lost to follow-up; M, month; PSP, pentamidine secondary prophylaxis; pt, patient; ToC, test of cure; VL, visceral leishmaniasis.
Figure 2.
Figure 2.
CD4 evolution after starting pentamidine secondary prophylaxis for Ethiopian visceral leishmaniasis/human immunodeficiency virus–coinfected patients who relapsed or remained relapse-free, 2011–2015 (N = 74). The evolution of CD4 counts over time was displayed using the nonparametric LOWESS smoothing method (lowess command in Stata).
Figure 3.
Figure 3.
Probability of relapse during and after pentamidine secondary prophylaxis in Ethiopian visceral leishmaniasis/human immunodeficiency virus–coinfected patients, 2011–2015 (N = 74).
Figure 4.
Figure 4.
Probability of relapse by history of visceral leishmaniasis (VL) during and after pentamidine secondary prophylaxis (PSP) for patients in Ethiopian VL/human immunodeficiency virus–coinfected patients, 2011–2015 (N = 74). Starting PSP after primary VL refers to “current” or “past” cases of VL starting prophylaxis after having suffered a first episode of VL. Those with a history of VL relapse when starting PSP were patients who had experienced at least 2 episodes of VL before starting prophylaxis.
Figure 5.
Figure 5.
Probability of relapse by baseline CD4 count during and after pentamidine secondary prophylaxis for patients in Ethiopian visceral leishmaniasis/human immunodeficiency virus–coinfected patients, 2011–2015 (N = 74).

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Source: PubMed

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