Previous visceral leishmaniasis relapses outperform immunological or clinical signs as predictors of further relapses in patients co-infected with HIV-1

Visceral leishmaniasis (VL) and HIV co-infection (VL/HIV) has emerged as a significant public health problem in Ethiopia, with up to 30% of VL patients co-infected with HIV. These patients suffer from recurrent VL relapses and increased mortality. Our aim was to assess whether VL/HIV co-infected patients with a previous history of VL relapses (recurrent VL/HIV) have a poorer prognosis as compared to HIV patients presenting with their first episode of VL (primary VL/HIV). Our results show that recurrent VL/HIV patients have a higher parasite load, higher mortality and that their relapse-free survival is significantly shorter. The poorer prognosis of recurrent VL/HIV patients is accompanied by lower weight gain and lower recovery of all blood cell lineages, as well as lower production of IFNγ, lower CD4+ T cell counts and higher expression levels of PD1 on T cells. Furthermore, our results show that prior history of VL relapse is an important risk factor for future relapse. Both CD4+ T cell count and parasite load were also associated with a higher risk of VL relapse, but neither of these was independently associated with relapse risk after adjustment for previous VL relapse history. We propose that in addition to the current treatments, novel interventions should be considered at the time of VL diagnosis in VL/HIV patients; and suggest that improved anti-leishmanial and antiretroviral treatments, as well as immune therapy, through PD1/PDL-1 blockade and/or through IFNγ administration, could result in more efficient parasite killing and thereby reduce the relapse rate and improve survival. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement YT is funded by a Wellcome Trust Training Fellowship in Public Health and Tropical Medicine (204797/Z/16/Z). This research was funded in part by the Wellcome Trust Grant [Grant number 206194, JAC]. For the purpose of Open Access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. MK is funded by a Wellcome Trust Sir Henry Wellcome Fellowship (206508/Z/17/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of the University of Gondar (IRB, reference O/V/P/RCS/05/1572/2017), the National Research Ethics Review Committee (NRERC, reference 310/130/2018) and Imperial College Research Ethics Committee (ICREC 17SM480) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript