Long term outcomes and prognostics of visceral leishmaniasis in HIV infected patients with use of pentamidine as secondary prophylaxis based on CD4 level: a prospective cohort study in Ethiopia

Abstract

Background: The long-term treatment outcome of visceral leishmaniasis (VL) patients with HIV co-infection is complicated by a high rate of relapse, especially when the CD4 count is low. Although use of secondary prophylaxis is recommended, it is not routinely practiced and data on its effectiveness and safety are limited.

Methods: A prospective cohort study was conducted in Northwest Ethiopia from August 2014 to August 2017 (NCT02011958). HIV-VL patients were followed for up to 12 months. Patients with CD4 cell counts below 200/μL at the end of VL treatment received pentamidine prophylaxis starting one month after parasitological cure, while those with CD4 count ≥200 cells/μL were followed without secondary prophylaxis. Compliance, safety and relapse-free survival, using Kaplan-Meier analysis methods to account for variable time at risk, were summarised. Risk factors for relapse or death were analysed.

Results: Fifty-four HIV patients were followed. The probability of relapse-free survival at one year was 50% (95% confidence interval [CI]: 35-63%): 53% (30-71%) in 22 patients with CD4 ≥200 cells/μL without pentamidine prophylaxis and 46% (26-63%) in 29 with CD4 <200 cells/μL who started pentamidine. Three patients with CD4 <200 cells/μL did not start pentamidine. Amongst those with CD4 ≥200 cells/μL, VL relapse was an independent risk factor for subsequent relapse or death (adjusted rate ratio: 5.42, 95% CI: 1.1-25.8). Except for one case of renal failure which was considered possibly related to pentamidine, there were no drug-related safety concerns.

Conclusion: The relapse-free survival rate for VL patients with HIV was low. Relapse-free survival of patients with CD4 count <200cells/μL given pentamidine secondary prophylaxis appeared to be comparable to patients with a CD4 count ≥200 cells/μL not given prophylaxis. Patients with relapsed VL are at higher risk for subsequent relapse and should be considered a priority for secondary prophylaxis, irrespective of their CD4 count.

Fig 1. Follow-up period flow diagram.

The maximum follow-up time was one year from initiation of VL treatment. However, patients only entered the cohort study on achieving negative parasitology. Hence, in general, patients had less than one year of follow-up in the cohort study.

Fig 2

Kaplan-Meier curve for relapse or death, for the two groups shown in Table 3: a) CD4 <200 cells/μL cells and pentamidine; and b) CD4 ≥200 cells/μL cells without pentamidine. Overall, the median follow-up time was 0.77 years (9.2 months, range: 0.16–1.00 years). Median (range) follow-up time; CD4 <200 cells/μL & pentamidine: 0.80 years (9.6 months, 0.16–0.99 years); CD4 ≥200 cells/μL, no pentamidine: 0.74 years (8.9 months, 0.19–1.00 years). Thus, by one year all but one of the patients had either relapsed (n = 21), died (n = 4), or been censored (n = 25). The short vertical lines above each of the Kaplan-Meier curves shows the times at which censoring occurred. A large proportion of patients were censored because the scheduled time of follow-up in the cohort was 390 days minus the time between initiation of VL treatment and achieving negative parasitology (see ‘Follow-up’ subsection of Methods). This figure shows proportions while the regression analysis in Table 4 is based on rates per person-year. The numerical values of the proportions differ from those of the rates, but the approaches are consistent and complementary, as explained in footnote g of Table 4.