Visceral Leishmaniasis In HIV-infected Patients Research Articles

Low Plasma Lipids Are Associated with Relapsing and Lethal Visceral Leishmaniasis in HIV-Infected Patients.

Visceral leishmaniasis (VL) results from protozoa Leishmania infantum and L. donovani infection. This study investigated whether host factors would explain the relapses. First, susceptibility to amphotericin B of L. infantum isolates was evaluated in vitro. Then, clinical data and the lipid profile of patients with relapsing and non-relapsing VL were assessed. Susceptibility to amphotericin B was similar between the isolates. CD4+ lymphocytes were reduced in both groups of patients in the first episode and with relapsing VL. Still, the strongest blood cell indicator associated with relapses was low total lymphocyte counts. Total plasma cholesterol, high-density lipoprotein, low-density lipoprotein, and, uniquely, triglycerides of the six individuals in the first episode and twenty-three with relapsing VL were lower in relapsing patients than those in the first episode. Deceased patients had extremely low low-density lipoprotein. After CD4+ decreases, lymphocyte CD8+ reduction is the final stage of immunological failure. The lower lipid concentrations appear to be secondary to the depletion of fat stores by inflammation-induced cachexia and fat exhaustion provoked by the co-occurrence of both diseases, which can finally lead to death.

Chronic High-Level Parasitemia in HIV-Infected Individuals With or Without Visceral Leishmaniasis in an Endemic Area in Northwest Ethiopia: Potential Superspreaders?

People with human immunodeficiency virus (PWH) with recurrent visceral leishmaniasis (VL) could potentially drive Leishmania transmission in areas with anthroponotic transmission such as East Africa, but studies are lacking. Leishmania parasitemia has been used as proxy for infectiousness. This study is nested within the Predicting Visceral Leishmaniasis in HIV-InfectedPatients (PreLeisH) prospective cohort study, following 490 PWH free of VL at enrollment for up to 24-37 months in northwest Ethiopia. Blood Leishmania polymerase chain reaction (PCR) was done systematically. This case series reports on 10 PWH with chronic VL (≥3 VL episodes during follow-up) for up to 37 months, and 3 individuals with asymptomatic Leishmania infection for up to 24 months. All 10 chronic VL cases were male, on antiretroviral treatment, with 0-11 relapses before enrollment. Median baseline CD4 count was 82 cells/µL. They displayed 3-6 VL treatment episodes over a period up to 37 months. Leishmania blood PCR levels were strongly positive for almost the entire follow-up (median cycle threshold value, 26 [interquartile range, 23-30]), including during periods between VL treatment. Additionally, we describe 3 PWH with asymptomatic Leishmania infection and without VL history, with equally strong Leishmania parasitemia over a period of up to 24 months without developing VL. All were on antiretroviral treatment at enrollment, with baseline CD4 counts ranging from 78 to 350 cells/µL. These are the first data on chronic parasitemia in PWH from Leishmania donovani-endemic areas. PWH with asymptomatic and symptomatic Leishmania infection could potentially be highly infectious and constitute Leishmania superspreaders. Xenodiagnosis studies are required to confirm infectiousness.

RELAPSING VISCERAL LEISHMANIASIS IN HIV INFECTED PATIENT WITH PERSISTENT LOW TCD4 COUNT: A CASE REPORT

Visceral leishmaniasis in HIV-infected patients is marked by a high mortality rate and its frequent relapses. It is characterized by the involvement of organs that are not usually affected in non-immunocompromised patients. We report a case of relapsing visceral leishmaniasis in an HIV-infected patient. HIV infection was discovered simultaneously as the first episode of visceral leishmaniasis. Even after recovery of visceral leishmaniasis and effective antiretroviral treatment with a negative viral load during three years, the TCD4 count remained low, contributing to visceral leishmaniasis relapse. The clinical presentation of the relapse was more severe and atypical, with renal and respiratory involvement leading to his death. Through this case and a literature review, we will discuss the relation between TCD4 count and visceral leishmaniasis in this coinfection.

A Flow Cytometry-Based Serological Assay to Detect Visceral Leishmaniasis in HIV-Infected Patients.

Visceral Leishmaniasis (VL) is a severe parasitic disease that has emerged as an important opportunistic condition in HIV-infected patients and whose control is impaired by inaccurate identification. This is mainly due to the serological tests used for VL having a reduced performance in cases of VL-HIV coinfection due to a low humoral response. In this situation, however, a positive test has even greater diagnostic value when combined with the clinical status. This study aimed to evaluate the application and performance of flow cytometry to detect anti-Leishmania infantum antibodies in HIV-infected patients. Sera from VL/HIV coinfected patients, characterized using “gold standard” techniques, were compared with sera from healthy controls plus sera from HIV-infected individuals. The flow cytometry results were expressed as levels of IgG reactivity, based on the percentage of positive fluorescent parasites (PPFP). A ROC curve analysis of a serum titration indicated a PPFP of 1.26% as being the cutoff point to segregate positive and negative results. At the 1:2,048 dilution, with 89% sensitivity and 83% specificity, flow cytometry showed greater sensitivity in relation to the serological tests evaluated. Futhermore, flow cytometry was the only assay that positively identified all VL-HIV patients with quantified HIV load. Together, these findings suggest that flow cytometry may be used as an alternative serological approach for VL identification and as a tool to characterize the humoral response against Leishmania infantum in HIV-infected patients.

Role of asymptomatic and symptomatic humans as reservoirs of visceral leishmaniasis in a Mediterranean context.

BackgroundIn the Mediterranean basin, Leishmania infantum is the causative agent of visceral leishmaniasis (VL), a zoonosis in which the dog is the primary domestic reservoir, although wildlife may have a leading role in the sylvatic cycle of the disease in some areas. Infections without disease are very frequent. There is limited information regarding the role that VL patients and asymptomatic infected individuals could be playing in the transmission of L. infantum. Xenodiagnosis of leishmaniasis has been used in this descriptive study to explore the role of symptomatic and asymptomatic infected individuals as reservoirs in a recent focus of leishmaniasis in southwestern Madrid, Spain.Methodology and main findingsAsymptomatic blood donors (n = 24), immunocompetent patients who were untreated (n = 12) or treated (n = 11) for visceral leishmaniasis (VL), and immunocompromised patients with VL (n = 3) were enrolled in the study. Their infectivity to Phlebotomus perniciosus was studied by indirect xenodiagnosis on peripheral blood samples. Quantitative polymerase chain reaction of blood samples from immunocompetent patients untreated for VL and immunocompromised untreated, treated and under secondary prophylaxis for VL was performed. Antibodies against Leishmania were studied by indirect fluorescent antibody and rK39-immunochromatographic tests. A lymphoproliferative assay with a soluble Leishmania antigen was used to screen for leishmaniasis infection in the healthy population. Sixty-two xenodiagnostic tests were carried out and 5,080 sand flies were dissected. Positive xenodiagnosis was recorded in four patients, with different sand fly infection rates: 1 immunosuppressed HIV / L. infantum coinfected asymptomatic patient, 1 immunosuppressed patient with multiple myeloma and symptomatic active VL, and 2 immunocompetent patients with untreated active VL. All blood donors were negative for both xenodiagnosis and conventional PCR.Conclusions / SignificanceThere is no consensus amongst authors on the definition of an ‘asymptomatic case’ nor on the tools for screening; we, therefore, have adopted one for the sake of clarity. Immunocompetent subjects, both infected asymptomatics and those treated for VL, are limited in number and appear to have no epidemiological relevance. The impact is limited for immunocompetent patients with untreated active VL, whilst immunosuppressed individuals undergoing immunosuppressive therapy and immunosuppressed individuals HIV / L. infantum coinfected were the most infectious towards sand flies. It is noteworthy that the HIV / L. infantum coinfected patient with asymptomatic leishmaniasis was easily infectious to sand flies for a long time, despite being under continuous prophylaxis for leishmaniasis. Accordingly, screening for latent Leishmania infection in HIV-infected patients is recommended in scenarios where transmission occurs. In addition, screening for VL in HIV-infected patients who have spent time in VL-endemic areas should also be implemented in non-endemic areas. More research is needed to better understand if some asymptomatic coinfected individuals contribute to transmission as ‘super-spreaders’.

Visceral leishmaniasis and HIV coinfection: current perspectives

Visceral leishmaniasis (VL) is caused by Leishmania donovani and Leishmania infantum. The burden of VL is concentrated in tropical and subtropical areas; however, HIV infection has spread VL over a hyperendemic area. Several outcomes are observed as a result of VL–HIV coinfection. Impacts are observed in immunopathogenesis, clinical manifestation, diagnosis, and therapeutic response. Concerning clinical manifestation, typical and unusual manifestation has been observed during active VL in HIV-infected patient, as well as alteration in immunoresponse, inducing greater immunosuppression by low CD4 T-lymphocyte count or even by induction of immunoactivation, with cell senescence. Serological diagnosis of VL in the HIV-infected is poor, due to low humoral response, characterized by antibody production, so parasitological methods are more recommended. Another important and even more challenging point is the definition of the best therapeutic regimen for VL in HIV-coinfected patients, because in this population there is greater failure and consequently higher mortality. The challenge of better understanding immunopathogenesis in order to obtain more effective therapies is one of the crucial points to be developed. The combination of drugs and the use of secondary prophylaxis associated with highly active antiretroviral therapy may be the best tool for treatment of HIV coinfection. Some derivatives from natural sources have action against Leishmania; however, studies have been limited to in vitro evaluation, without clinical trials.

Comparison of Parasitological, Serological, and Molecular Tests for Visceral Leishmaniasis in HIV-Infected Patients: A Cross-Sectional Delayed-Type Study

The aim of this study was to evaluate the accuracy of invasive and non-invasive tests for diagnosis of visceral leishmaniasis (VL) in a large series of human immunodeficiency virus (HIV)-infected patients. In this delayed-type cross-sectional study, 113 HIV-infected symptomatic patients were evaluated by an adjudication committee after clinical follow-up to establish the presence or absence of VL as the target condition (reference test). The index tests were recombinant K39 antigen-based immunochromatographic test (rK39), indirect fluorescent antibody test (IFAT), prototype kit of direct agglutination test (DAT-LPC), and real-time polymerase chain reaction (qPCR) in peripheral blood. Compared with parasitological test and adjudication committee diagnosis or latent class model analyses, IFAT and rk39 dipstick test presented the lowest sensitivity. DAT-LPC exhibited good overall performance, and there was no statistical difference between DAT-LPC and qPCR diagnosis accuracy. Real-time PCR emerges as a less invasive alternative to parasitological examination for confirmation of cases not identified by DAT.

Ultrasensitive Real-Time PCR for the Clinical Management of Visceral Leishmaniasis in HIV-Infected Patients

Molecular methods have been proposed as an alternative tool for the diagnosis of visceral leishmaniasis (VL), but no data are available regarding use for monitoring clinical outcome. A prospective cohort study of human immunodeficiency virus-(HIV) and VL-coinfected patients was conducted in a university-affiliated hospital in Barcelona, Spain. Leishmania parasite load was monitored using a real-time polymerase chain reaction (PCR) at baseline and every 3 months. Cutoff values for PCR were determined using receiver operating characteristic (ROC) curves. Overall, 37 episodes were analyzed, and 25 of these episodes were considered as relapsing episodes. A significant decrease of parasite load measured 3 months after treatment could predict the clinical evolution of VL. A parasite load over 0.9 parasites/mL measured 12 months after treatment could predicts relapse with a sensitivity of 100% and a specificity of 90.9%. Monitoring parasite load by an ultrasensitive quantitative Leishmania PCR is useful to predict the risk of relapse after a VL episode in HIV-infected patients.

HIV-1 protease inhibitors for treatment of visceral leishmaniasis in HIV-co-infected individuals

The global prevalence of HIV is a major challenge for control of visceral leishmaniasis, a disseminated protozoan infection. In some east African regions, up to 40% of patients with visceral leishmaniasis are co-infected with HIV. Management of visceral leishmaniasis in such patients is complicated by treatment failures and relapses, even while patients are receiving standard antiretroviral therapy. In-vitro studies have consistently documented an inhibitory effect of specific HIV-1 protease inhibitors on leishmania parasites, and the underlying mechanism is partly explained. With the global scaling up of HIV treatment, HIV-1 protease inhibitors are increasingly becoming available for second-line HIV treatment in regions where visceral leishmaniasis and HIV are endemic. However, additional research is needed before HIV-1 protease inhibitors can be taken forward for clinical use against visceral leishmaniasis in HIV-infected patients. Since the effect of protease inhibitors against Leishmania species was generally observed at high drug concentrations, efficacy and dose-response relationships should be studied in animals before these drugs are used in clinical trials. More extensive studies of all available HIV protease inhibitors are needed, including investigation of drug interactions and emergence of drug-resistant parasites. In addition to exploring the full potential of current HIV-1 protease inhibitors against visceral leishmaniasis, leishmania-specific protease inhibitors should be developed.

Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients--authors' response

Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients--authors' response

Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients

Visceral leishmaniasis (VL) is characterized by frequent relapses in HIV-infected patients, even in those who receive secondary prophylaxis. The aim of our study was to evaluate the efficacy of liposomal amphotericin B (L-AMB) for secondary prophylaxis of VL in HIV-infected patients. From January 2001 to December 2005, 17 HIV patients, with at least one previous episode of VL who received L-AMB as secondary prophylaxis for VL, were included in the study. Efficacy was measured as the proportion of patients remaining free (non-relapse) of VL at different time points. Relapses were analysed as time-to-relapse distribution and were evaluated by survival analysis using the Kaplan-Meier method. Twenty-one episodes of VL were diagnosed and nine relapsed. The median follow-up time was 14 (5-44) months. The probability of remaining free of relapse at 6 months was 89.7% (95% CI, 76.2-100); at 12 months, the probability was 79.1% (95% CI, 61-97.2) and at 24 and 36 months, the probability was 55.9% (95% CI, 30.5-81.3). In the non-relapsing group, patients had a significant increase in CD4 cell levels of 102 (10-174) and 126 (4-159) cells/mm(3) at 12 and 24 months, respectively (P = 0.037), whereas in the relapsing group, no significant increase was observed. Prophylaxis with L-AMB was well tolerated and only three patients had a mild impairment of renal function without requiring any change in treatment. L-AMB is well tolerated and useful for secondary prophylaxis of VL.

Central role of interleukin-15 in human immunodeficiency virus (HIV)-infected patients with visceral leishmaniasis

To evaluate clinical and immunological parameters, interleukin (IL)-15 production and outcome of patients with visceral leishmaniasis (VL), including HIV positive patients, we analyzed 48 cases of VL. Clinical manifestations and response to therapy were similar in VL/HIV− and VL/HIV+ patients. However, relapses were more frequent in patients with HIV infection. Low levels of IL-15 concentrations were found in HIV+ patients without VL. These levels were comparable to concentrations obtained in healthy donors. We found a relationship between response to therapy and IL-15 levels. We found increased levels of IL-15 in VL/HIV− and VL/HIV+ patients with clinical and parasitological response to therapy. Our data demonstrate that VL in HIV-infected patients occurs in subjects with severe immunodeficiency and presents high rate of relapses. Low levels of IL-15 in illness patients and restored production in cured persons suggest that this cytokine could play a central role in immune responses during Leishmania/HIV co-infection.

Leishmaniasis as an opportunistic infection in HIV-infected patients: determinants of relapse and mortality in a collaborative study of 228 episodes in a Mediterreanean region

The clinical presentation of visceral leishmaniasis shares similarities with other geographically specific infectious diseases associated with AIDS in terms of relapsing course and atypical presentation. However, visceral leishmaniasis has not, until now, been included in the AIDS case definition. The aim of this study was to describe the clinical features and determinants for relapse and case-fatality of visceral leishmaniasis in HIV-infected patients from a Spanish Mediterranean area. A chart review was conducted in 16 hospitals in the autonomous communities of Valencia and Murcia (Spain). From 1988 to 2001, a total of 228 episodes of visceral leishmaniasis were diagnosed in 155 HIV-infected patients by the detection of amastigotes in bone marrow aspirates or in other tissue samples. Most patients had advanced HIV disease, with a median CD4(+) lymphocyte cell count of 55 cells x 10(9) l, and 56% of them had a previous AIDS-indicator disease. The median duration of follow-up was 8.4 months. HIV-infected patients with visceral leishmaniasis presented with fever (76%), hepatomegaly (77%), splenomegaly (78%), and varying degrees of cytopenias. Leishmania was detected in atypical sites in 22 (14%) patients. A total of 37 (24%) patients had a relapse of visceral leishmaniasis. Female gender was a risk factor for relapse, whereas administration of secondary prophylaxis for visceral leishmaniasis and a completed therapy for visceral leishmaniasis were protective factors against relapse. A total of 86 (54%) patients died. Independent determinants for survival were CD4(+) lymphocyte cell count, completed therapy for leishmania, and secondary prophylaxis for visceral leishmaniasis. The findings show that, in HIV-infected patients, visceral leishmaniasis occurs in late stages of HIV disease and often has a relapsing course. Secondary prophylaxis reduces the risk of relapse. Visceral leishmaniasis in the HIV-infected population should be included in the CDC clinical category C for the definition of AIDS in the same way that other geographically specific opportunistic infections are included.

Highly Active Antiretroviral Therapy (HAART) Modifies the Incidence and Outcome of Visceral Leishmaniasis in HIV-Infected Patients

Highly Active Antiretroviral Therapy (HAART) Modifies the Incidence and Outcome of Visceral Leishmaniasis in HIV-Infected Patients

Incidence of and risk factors for symptomatic visceral leishmaniasis among human immunodeficiency virus type 1-infected patients from Spain in the era of highly active antiretroviral therapy.

The way in which the extensive use of highly active antiretroviral therapy (HAART) has influenced the incidence of visceral leishmaniasis (VL) among human immunodeficiency type 1 (HIV-1)-infected patients is not yet understood. The present study assessed whether the incidence of symptomatic VL in HIV-infected patients has decreased since the introduction of HAART. Likewise, the role of other potential risk factors for VL was also analyzed. Therefore, 479 HIV-1-infected patients receiving antiretroviral treatment, according to the available drugs at each moment, were prospectively followed from April 1989 to June 2000 in two university hospitals in southern Spain. A bone marrow aspiration was performed when patients showed symptoms suggestive of kala-azar. A diagnosis of VL was made when Leishmania amastigotes were seen in Giemsa-stained samples or promastigotes were cultured in specific media. The median follow-up time was 1,380 [8 to 4,536] days. Twenty-one patients were diagnosed with symptomatic VL. The density of incidence of VL has decreased 64.8% as of January 1997, when HAART began to be used extensively in our area. The use of HAART was the main independent factor associated with VL; this therapy was a protective factor (adjusted hazard ratio [HR], 0.05; 95% confidence interval [CI], 0.02 to 0.15). CDC clinical category C at entry in the cohort (HR, 4.08; 95% CI, 1.46 to 11.35) and CD4(+) cell counts below 300 cells/mm(3) during the follow-up (HR, 3.96; 95% CI, 1.56 to 10.01) were also independently associated with kala-azar. A VL diagnosis prior to follow-up and low compliance with antiretroviral therapy were not independently associated with symptomatic VL, although statistical significance was almost reached (P = 0.1 and P = 0.08, respectively). In summary, the use of HAART has led to a fall in the incidence of symptomatic VL in HIV-infected patients. The main risk factor associated with kala-azar emergence in patients infected with HIV is deep immunosuppression.

Relapsing visceral leishmaniasis in HIV-infected patients undergoing successful protease inhibitor therapy.

The aim of this study was to establish the evolution of visceral leishmaniasis (VL) in 10 consecutive patients coinfected with VL and HIV, taking into account the decline in the incidence of opportunistic infections after the introduction of protease inhibitor therapy. During a median follow-up of 31 months, 7 (70%) of 10 patients relapsed. The incidence of relapse was slightly lower than before institution of protease inhibitor therapy (20 vs. 13 patient-months), with a 31% probability that relapse would not have taken place within 2 years. VL relapses occurred even though increases in the CD4+ cell counts were observed and HIV loads were undetectable, suggesting that successful antiretroviral therapy is not sufficient to control the disease. Relapsing patients also had a lower increase in the CD4+ cell count.

Highly active antiretroviral therapy decreases the incidence of visceral leishmaniasis in HIV-infected individuals.

In Mediterranean countries visceral leishmaniasis (VL) is a zoonosis caused by the protozoon Leishmania infantum. In the early 1990s, the incidence of VL increased in southern European countries, probably because of the increased number of cases that occurred in patients with HIV infection [1]. Recently, highly active antiretroviral therapy (HAART), using a combination of protease inhibitors and reverse transcriptase inhibitors [2], has been demonstrated not only to have a powerful activity on HIV, as shown by the reduction in plasma HIV RNA and the increase in peripheral CD4 cells, but also to cause a drop in the incidence of opportunistic infections and deaths [3,4]. However, no data are presently available on the effect, if any, of HAART on the incidence of VL in HIV-infected individuals. Therefore, the aim of this study was to assess the incidence of VL, before and after the introduction of HAART, as standard therapy in HIV-infected patients in a large cohort of Italian HIV-infected subjects. In particular, we performed a 9 year (1991–1999) retrospective cohort study considering all cases of VL admitted to the Department of Infectious Diseases of a large university hospital in Rome, Italy. Over the study period, we observed 36 cases of leishmaniosis, 20 cases (55%) in HIV-infected patients and 16 (35%) in immunocompetent individuals. For a better evaluation of the differences in VL incidence in HIV-infected patients attributed to HAART, two periods of time were compared: January 1991–December 1995 (period A), and January 1997–December 1999 (period B). HAART became the standard of care in the majority of our patients after September 1996, when protease inhibitors became available in Italy, and for this reason we have not considered, in the statistical analysis, cases of VL occurring in 1996. In particular, we observed 18 episodes of VL in period A and 13 in period B. HIV infection was present in 78% (14/18) of the total VL cases observed in period A and in 15% (2/13) in period B (P < 0.01; odds ratio 19.25; 95% confidence interval 2.37–220.18). Comparing the incidence of VL in HIV-infected patients in periods A and B, a statistically significant reduction in the incidence of VL, from 0.7 episodes per 100 person/years to 0.13 episodes per 100 person/years, was observed (P < 0.01; odds ratio 5.25; 95% confidence interval 1.20–47.65). The majority of HIV-infected patients with VL were men (72%) and in the C3 category of HIV infection (75%) without any significant statistical differences between period A and period B. The mean number of peripheral CD4 cells was 54/mm3 (range 1–207/mm3). The mean level of plasma HIV RNA, available in patients observed in period B only, was 105 000 copies/ml. The analysis of risk factors for VL, including the geographical area of origin of the patients, did not differ significantly between the two study periods. In conclusion, our study confirms that HIV is a relevant predisposing condition for VL, in Italy as well as in other Mediterranean countries [5,6], and indicates, as a novel observation, a significant decrease in the incidence of VL in HIV-infected patients after the introduction of HAART. The reduction in the incidence of VL is probably the consequence of the well-known immune restoration induced by HAART [2], as witnessed by the increase in median peripheral CD4 cell counts and the decrease in HIV viraemia (data not shown). Such a reduced incidence of VL in HIV-infected patients could have a substantial impact on future morbidity and health costs in Mediterranean countries as well as in other geographical areas where VL is endemic. Mario Tumbarello Evelina Tacconelli Silvia Bertagnolio Roberto Cauda

Itraconazole as Maintenance Therapy for Visceral Leishmaniasis in HIV-Infected Patients

Itraconazole as Maintenance Therapy for Visceral Leishmaniasis in HIV-Infected Patients

Itraconazole as maintenance therapy for visceral leishmaniasis in HIV-infected patients.

Itraconazole as maintenance therapy for visceral leishmaniasis in HIV-infected patients.

Successful Treatment of Antimony-Resistant Visceral Leishmaniasis with Liposomal Amphotericin B in Patients Infected with Human Immunodeficiency Virus

We describe two cases of visceral leishmaniasis in patients infected with human immunodeficiency virus (HIV); both cases were resistant to antimony compounds but were cured with liposomal amphotericin B, with no significant toxicity. A review of the previous reported cases of antimony-resistant visceral leishmaniasis in HIV-infected patients confirmed the effectiveness of treatment with liposomal amphotericin B, which directly targets infected macrophages and reaches high levels in plasma and tissue.