Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients

Abstract

Patients with visceral leishmaniasis (VL)–human immunodeficiency virus (HIV) coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients respond poorly to conventional VL treatment and play an important role in parasite transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic drugs, new interventions that target host immunity may offer an effective alternative. In this review, we first summarize current views on how VL immunopathology is significantly affected by HIV coinfection. We then review current clinical and promising preclinical immunomodulatory interventions in the field of VL and discuss how these may operate in the context of a concurrent HIV infection. Caveats are formulated as these interventions may unpredictably impact the delicate balance between boosting of beneficial VL-specific responses and deleterious immune activation/hyperinflammation, activation of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to prioritize a target molecule and a more detailed account of the immunological status induced by the coinfection as well as surrogate markers of cure and protection are still required. We do, however, argue that virologically suppressed VL patients with a recovered immune system, in whom effective antiretroviral therapy alone is not able to restore protective immunity, can be considered a relevant target group for an immunomodulatory intervention. Finally, we provide perspectives on the translation of novel theories on synergistic immune cell cross-talk into an effective treatment strategy for VL–HIV-coinfected patients.

Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation

“…This indicates that impaired IFN-γ functioning does not only hamper normal immune function but also limits miltefosine’s action to stimulate macrophage-driven Th1 cytokine production. The importance of restoring the host immunity in VL is particularly demonstrated in immunosuppressed patients, such as those who are coinfected with human immunodeficiency virus (HIV), where VL is even more challenging to treat and results in more episodes of relapse and even death (58). Furthermore, neopterin, a Th1 immune marker, has been recently evaluated in VL patients after treatment with miltefosine alone or in combination with amphotericin B (59).…”

“…Additionally, miltefosine-induced immunomodulation may particularly be important for patients who are coinfected with HIV. In this immunocompromised patient population suffering from both HIV and VL, the immune responses are heavily dominated by Th2 cytokine activity, and combined with antiretroviral treatment, miltefosine was proven to have relatively high efficacy (58, 72).…”

Parâmetros Clínicos, Diagnóstico E Tratamento Da Leishmaniose Tegumentar E Visceral

“…A pentoxifilina é um fármaco da classe de vasodilatadores periféricos com propriedades hemorreológicas. A imunossupressão contribui significativamente para o número de casos de leishmaniose, principalmente a visceral (ADRIAENSEN et al, 2018;AKUFFO et al, 2018). Estudos demonstram sucesso no emprego da pentoxifilina como coadjuvante (imunomodulador) no tratamento da leishmaniose tegumentar, levando a cura mais rapidamente quando comparado ao tratamento convencional (BRITO et al, 2017;BERBERT et al, 2018).…”

Asymptomatic immune responders to Leishmania among HIV positive patients

“…Similarly, active Leishmania infection can increase the replication of the virus, encouraging progression to full-blown acquired immunodeficiency syndrome (AIDS) [4]. In the pre-HAART (highly active antiretroviral therapy) era, patients with HIV also infected with Leishmania commonly developed VL; these days, however, the efficiency of HAART allows a variable proportion of such patients to remain asymptomatic [8, 10].…”