Immunological factors, but not clinical features, predict visceral leishmaniasis relapse in patients co-infected with HIV

Abstract

Visceral leishmaniasis (VL) has emerged as a clinically important opportunistic infection in HIV patients, as VL/HIV co-infected patients suffer from frequent VL relapse. Here, we followed cohorts of VL patients with or without HIV co-infections in Ethiopia and collected detailed clinical and immunological data during 12 months of follow-up. By the end of the study 78.1% of VL/HIV patients, but none of the VL only patients, had relapsed. Despite clinically defined cure, VL/HIV patients maintained high parasite loads, low BMI, hepatosplenomegaly and pancytopenia throughout follow-up. During detailed immunological study throughout the follow-up period, we identified three markers associated with VL relapse: i) failure to restore antigen-specific production of IFNγ, ii) persistently low CD4+ T cell counts, and iii) high expression of PD1 on CD4+ T cells. We show that these three markers combine well in predicting VL relapse, and that all three measurements are needed for optimal predictive power. These three immunological markers can be measured in primary hospital settings in Ethiopia and can predict VL relapse after anti-leishmanial therapy. The use of our prediction model has the potential to improve disease management and patient care.

Diversity and within-host evolution of parasites from VL and VL/HIV patients in Northern Ethiopia

“…While we cannot exclude the possibility that specific groups of strains may have a higher propensity to infect HIV positive patients, we propose that this is likely to be due to geographic structure in the parasite population that is correlated with geographic differences in HIV prevalence. Many of the VL patients in this region of Ethiopia (Gadisa et al 2015) -including 84.8% of the patients in this cohort (Takele et al 2021) -are migrant workers who move from non-endemic regions for seasonal agricultural work. Possibly due to their non-endemic origin and the working and living conditions on the farms they are frequently infected with Leishmania and develop clinical VL.…”

“…Informed written consent was obtained from each patient. The patients were all recruited at the time of VL diagnosis (ToD) at the Leishmaniasis Research and Treatment Center in Gondar, Amhara National Regional State, Ethiopia between December 2017 and May 2019 and were each followed up for three years (Takele et al 2021).…”

“…The genome-wide haploid coverage of the sequenced samples ranged between 7 and 30 (median 13). Our study included 68 patients, who had VL only, and 29 patients were additionally coinfected with HIV and were receiving antiretroviral treatment (Takele et al 2021). The complete metadata of samples taken, technical replicates and patients is summarised in table S1.…”

“…These parasites were isolated from a cohort of VL patients in which 78.1% of the successfully treated VL/HIV patients relapsed within a three-year time period, while none of the patients without HIV infection relapsed (Takele et al 2021). Therefore, we tested for the possibility that there is a genetic difference between parasites isolated from HIV negative vs. HIV positive VL patients that could explain this difference in relapse rate.…”

“…Extensive clinical and immunological data was collected from these patients over 12 months of follow-up, and long-term outcomes recorded up to 3 years post VL diagnosis, so the parasite genome data we report is from a well-understood patient population. Full details of patient recruitment and clinical data from these patients have previously been reported (Takele et al 2021). Parasite isolation is generally only possible when either bone marrow or splenic aspirates are being performed for parasitological investigation, which is routinely done at diagnosis of each VL episode.…”