Juan Delgado

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

ABSTRACT 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/mm3 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.

Influence of hepatitis C virus infection on the mortality of antiretroviral-treated patients with HIV disease

The aims of this study were to analyze the mortality directly attributable to chronic viral hepatitis in HIV-1 infected patients and to investigate the influence of hepatitis virus infections on the survival of this population. A cohort of 328 HIV-1 infected, antiretroviral-treated patients, followed up from 1989 to 1996, was investigated in the study. The median follow-up period of the cohort was 120 weeks. The median baseline CD4+cell count of the cohort was 303 cells/mm3. Hepatitis C virus, hepatitis B virus and hepatitis D virus infections were present in 214 (65%), 16 (4.9%) and 9 (2.7%) patients, respectively. Sixty-seven (20.4%) subjects died but there was no information on the vital status of 36 patients (11%). The causes of mortality were AIDS in 49 (73%), liver failure in 3 (4.5%) and other causes in 15 (22.4%). The cohort was divided into two groups for survival analysis, the groups consisting of persons infected by a hepatitis virus and persons without hepatitis virus infection. There was no difference in survival between the two groups (p=0.31, log-rank). It is concluded that mortality among HIV-1/hepatitis virus coinfected patients with moderate to severe immunosuppression is mostly due to AIDS, and that the survival of these subjects is not influenced by the presence of hepatitis virus infections, particularly hepatitis C virus.

Influence of Highly Active Antiretroviral Therapy on the Outcome of Subclinical Visceral Leishmaniasis in Human Immunodeficiency Virus-Infected Patients

Seventeen human immunodeficiency virus-infected patients who were harboring untreated subclinical visceral leishmaniasis (VL) were prospectively followed up. None of the 11 patients who received highly active antiretroviral therapy (HAART) presented with symptomatic VL during follow-up, whereas 2 out of 6 patients who received therapy other than HAART had an episode of overt kala-azar. These findings suggest that HAART does not induce the evolution of latent VL into symptomatic disease.

Symptomatic Elevations of Lactic Acid and Their Response to Treatment Manipulation in Human Immunodeficiency Virus—Infected Persons: A Case Series

Symptomatic lactic acidemia was seen in 5 human immunodeficiency virus-positive patients receiving combination therapy that included stavudine and > or =1 other nucleoside. Peak venous lactic acid levels of 3.1-7.4 mmol/L (normal range, 0.5-2.1 mmol/L) were associated with fatigue and rapid weight loss, whereas withdrawal of antiretrovirals led to normalization of venous lactic acid levels, symptomatic improvement, and weight gain. Resumption of an altered therapeutic regimen, which did not include stavudine but did include other nucleosides in 4 of 5 cases, did not result in recurrence of the syndrome after up to 126 days.

The high sensitivity of a PCR- ELISA in the diagnosis of cutaneous and visceral leishmaniasis caused by Leishmania infantum

Abstract In general, the conventional techniques available for the diagnosis of leishmaniasis have relatively low sensitivity. This means that parasite-rich samples (which can usually only be collected by very invasive methods, such as bone-marrow aspiration) must be employed. This problem has not yet been solved even by use of the PCR-based techniques currently available. However, a new PCR-ELISA has been developed for the diagnosis of cutaneous (CL) and visceral leishmaniasis (VL) caused by Leishmania infantum. This assay appears to have sufficient sensitivity to be effective in the diagnosis of VL not only when bone-marrow aspirates are investigated but also when the samples are of peripheral blood. Overall, the ability of the PCR-ELISA to detect Leishmania, in 76 samples (22 of peripheral blood, 36 bone-marrow aspirates and 18 skin samples) from 72 patients living in a endemic region, was better than that of culture or the examination of Giemsa-stained smears. For example, L. infantum kDNA was detected by PCR-ELISA in 15 (83%) of the 18 skin samples from suspected cases of CL, whereas the combined use of several classical techniques only confirmed the presence of amastigotes in five (28%) of these samples. Similarly, only 21 individuals were diagnosed as having VL by conventional techniques whereas 30 were found Leishmania-positive in the PCR-ELISA. The new PCR-ELISA also appears to be a suitable technique for detecting leishmanial kDNA in samples of peripheral blood from cases of L. infantum-HIV co-infection. The assay is more sensitive than the combined use of several conventional techniques in the diagnosis of subclinical VL, probably because those with subclinical infection have relatively low parasitic loads that are generally undetectable using the other techniques.

Evidence of Thymic Function in Heavily Antiretroviral-Treated Human Immunodeficiency Virus Type 1–Infected Adults with Long-Term Virologic Treatment Failure

Thymic function was evaluated in 32 heavily antiretroviral-treated human immunodeficiency virus type 1 (HIV-1)-infected adults with long-term virologic treatment failure by measuring thymic volume, by determining the absolute number of naive T cell phenotypes, and by determining the number of cells carrying T cell receptor excision circles (TRECs). There was a significant inverse correlation between age and thymic volume (r=-0.415; P=.018), and there was a significant direct correlation between thymic volume and total naive T cell counts (r=0.529; P=.002), naive CD4(+) cell counts (r=0.437; P=.012), naive CD8(+) cell counts (r=0.467; P=.007), and TREC levels (r=0.391; P=.027). In conclusion, this study found clear evidence that the thymus of heavily antiretroviral-treated HIV-1-infected adults with long-term virologic treatment failure is actively engaged in thymopoiesis, which generates new naive T cells for the peripheral lymphocyte pool.

TNF-α levels in HIV-infected patients after long-term suppressive cART persist as high as in elderly, HIV-uninfected subjects

BACKGROUND Chronic and systemic inflammatory alterations occur in HIV-infected patients and elderly uninfected subjects and in both scenarios these alterations are associated with the development of chronic morbidities and mortality. However, whether the levels of inflammatory alterations in untreated HIV-infected patients and elderly individuals are similar is unknown. Moreover, whether long-term antiretroviral therapy normalizes inflammatory alterations compared with HIV-uninfected persons of different age is not known. METHODS We analysed soluble inflammatory levels [high-sensitivity C-reactive protein, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8 and IL-17] in a cohort of viraemic HIV-infected patients compared with (i) age-matched, (ii) elderly and (iii) non-survivor elderly, uninfected healthy controls. We longitudinally analysed the effect of long-term 48 and 96 week suppressive combined antiretroviral therapy (cART) on the soluble inflammatory levels compared with those found in control subjects. RESULTS Baseline IL-6 and IL-8 levels were at similar or lower concentrations in untreated patients compared with healthy elderly individuals. However, TNF-α and IFN-γ levels broadly exceeded those found in survivors and non-survivor elderly individuals. Long-term suppressive cART normalized most of the inflammatory markers, with the exception of TNF-α levels, which persisted as high as those in elderly non-survivor controls. CONCLUSIONS Chronic inflammatory alterations associated with HIV infection are maintained at a different level from those of ageing. The persistent alteration of TNF-α levels in HIV-infected patients might cause tissue damage and have implications for developing non-AIDS-defining illnesses, even when HIV replication is long-term controlled by cART.

Evidence of increased risk for leishmania infantum infection among HIV-seronegative intravenous drug users from southern Spain.

Abstract To assess the prevalence of markers of Leishmania infection, 93 intravenous drug users and 77 non-users of intravenous drugs underwent a Leishmania skin test and a serum Leishmania antibody search. All participants were human immunodeficiency virus seronegative. The Leishmania skin test was positive in 24 intravenous drug users and in 10 non-users of intravenous drugs (P=0.038). Leishmania seropositivity was detected in 3 of 11 active intravenous drug users and in 3 of 82 former drug injectors (P=0.02). Positivity in the Leishmania skin test was associated with intravenous drug use (adjusted odds ratio, 2.33; 95% confidence interval, 1.03–5.24). The prevalence of Leishmania infection markers among intravenous drug users is higher than that among controls. This suggests that this parasite spreads through the sharing of needles.

HIV-1 Plasma Viremia not Increased in Patients Receiving Highly Active Antiretroviral Therapy After Influenza Vaccination

Abstract The effect of vaccinating patients with sustained undetectable HIV-1 viremia (VL) achieved with highly active antiretroviral therapy was prospectively investigated. During the 1998 influenza immunization period, 39 HIV-1-infected patients who showed a VL<20 copies/ml for at least 6 months before the study entry date were vaccinated for influenza. Twenty-two vaccinees were immunized at entry. Seventeen controls were followed for 4 weeks after entry, crossing over then to the vaccination group. The proportion of patients with undetectable VL was not significantly different between the vaccination and control groups 2 and 4 weeks after entry. Therefore, influenza immunization of patients with undetectable viremia achieved with highly active antiretroviral therapy does not seem to affect VL.

IFNγ−TNFα−IL2−MIP1α−CD107a+PRF1+ CD8 pp65-Specific T-Cell Response Is Independently Associated With Time to Death in Elderly Humans

Persistent cytomegalovirus (CMV) infection has been suggested to be a major driving force in the immune deterioration and an underlying source of age-related diseases in the elderly. CMV antibody titers are associated with lower responses to vaccination, cardiovascular diseases, frailty, and mortality. CMV infection is also associated with shorter T-cell telomeres and replicative senescence. Although an age-related deregulation of CMV-specific T-cell responses could be an underlying cause of the relationship between CMV and immune defects, strong and polyfunctional responses are observed in elderly individuals, casting uncertainty on their direct role in age-related immune frailty. In this study, we longitudinally followed a cohort of healthy donors aged over 50 years, assessing their mortality rates and time to death during a 2-year period. Specific T-cell responses to the immunodominant antigen pp65 (IFNγ, TNFα, IL2, MIP1α, CD107a, and perforin production) were analyzed at the beginning of the 2-year observation period. A cytotoxic CD8 pp65-specific T-cell response, without cytokine or chemokine coexpression, was independently associated with all-cause mortality in these elderly individuals. This pp65-specific CD8 T-cell response could be a useful tool to identify individuals with depressed immune function and a higher risk of death.