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Purpose Cases of persistent infection have already been widely described with some proposals for combination or extended course therapies in immunocompromised subjects, but nothing has been addressed in AIDS patients. We present a case of prolonged, mild SARS-CoV-2 infection that was successfully treated with a consecutive combined scheme of therapy. Methods/Results A prolonged shedding of SARS-CoV-2 was observed up to 92 days and the COVID-19 clinical manifestation was mild without evidence of pneumonia and/or acute respiratory insufficiency. The infection was not cleared after the first treatment with remdesivir IV as early treatment (for 3 days) suggesting a limited effect on SARS-CoV-2 in an immunocompromised individual. Several weeks later, a second therapeutic attempt was made with tixagevimab/cilgavimab 300/300 IM but SARS-CoV-2 RNA was still detected for further 5 weeks. A third attempt with nirmatrelvir/ritonavir determined the definitive viral clearance of SARS-CoV-2 after 92 days since the first detection. Conclusion Our data indicate that certain immunocompromised individuals may shed infectious virus longer and need a tailored and valuable therapeutics approach. Additional data from clinical trials are required to support a feasible approach to managing this vulnerable group of patients.

Background Data on SARS-CoV-2 vaccine immunogenicity in PLWH are currently limited. Aim of the study was to investigate immunogenicity according to current CD4 T-cell count Methods PLWH on ART attending a SARS-CoV-2 vaccination program, were included in a prospective immunogenicity evaluation after receiving BNT162b2 or mRNA-1273. Participants were stratified by current CD4 T-cell count (poor CD4 recovery, PCDR: 500/mm3). RBD-binding IgG, SARS-CoV-2 neutralizing antibodies (nAbs) and IFN-γ release were measured. As control group, HIV-negative healthcare workers (HCWs) were used Findings Among 166 PLWH, after 1 month from the booster dose, detectable RBD-binding IgG were elicited in 86.7% of PCDR, 100% of ICDR, 98.7% of HCDR, and a neutralizing titre ≥1:10 elicited in 70.0%, 88.2%, and 93.1%, respectively. Compared to HCDR, all immune response parameters were significantly lower in PCDR. After adjusting for confounders, current CD4 T-cell Conclusion Humoral and cell-mediated immune response against SARS-CoV-2 were elicited in most of PLWH, albeit significantly poorer in those with CD4 T-cell 500 cell/mm3 and HIV-negative controls. A lower RBD-binding antibody response than HCWs was also observed in PLWH with CD4 T-cell 200–500/mm3, whereas immune response elicited in PLWH with a CD4 T-cell >500/mm3 was comparable to HIV-negative population

Background Few data about predictors and outcomes associated with prolonged SARS-CoV-2 RNA shedding (VS) are available. Methods Retrospective study including all patients admitted with COVID-19 in an Italian reference hospital for infectious diseases between March 1 and July 1, 2020. Predictors of viral clearance (VC) and prolonged VS from upper respiratory tract were assessed by Poisson regression and logistic regression analyses. The causal relation between duration of VS and probability of clinical outcomes was evaluated through inverse probability weighted Cox model. Results 536 subjects were included. Median duration of VS from symptoms onset was 18 days (IQR 12-26). The estimated 30-day probability of VC was 70.2% (95%CI:65-75). At multivariable analysis, patients with comorbidities (aIRR = 0.88, p = 0.004), lymphopenia at hospital admission (aIRR = 0.75, p = 0.032) and with moderate/severe respiratory disease (aIRR = 0.42, p 1000 ng/mL at admission (aOR = 1.76, p = 0.035) independently predicted prolonged VS. The achievement of VC doubled the chance of clinical recovery (aHR = 2.17, p

Historically, older patients have shown a higher risk of HIV-1-associated dementia (HIVD). The objective of this study was to evaluate the association of aging with HIVD and minor cognitive motor disorders (MCMDs) during the late-highly active antiretroviral therapy (HAART) era and to analyze characteristics, predictive factors, and survival of older HIV-1-infected individuals affected by these disorders. A nested longitudinal study was designed for a cohort of HIV-1-infected individuals with neurological diseases. Multiple logistic regression and Cox regression for survival were employed. From 2000 to 2003, 195 patients with HIVD (53%) or MCMD (47%) were enrolled. The cumulative prevalence of these two disorders was 21%, with an increasing rate for calendar year (p0.001). Previous antiretroviral exposure occurred in 46% of patients. Mean CD4(+) cell count and plasma HIV-1 RNA were 144 cells/microl and 4.5 log10 copies/ml, respectively. The mean age was 44 years (SD, 9.9), with 35% of patients aged 20-39 years (I), 45% aged 40-49 years (II), and 20% aged/=50 years (III). Among drug-naive patients, the prevalence of HIVD progressively increased in older subjects: 7.2% (I), 15.3% (II), and 27.3% (III) (p0.001), whereas no significant increase in HIVD with older age was observed in drug-treated subjects. Older age was independently associated with an increased risk of HIVD (odds ratio, 6.44; 95% confidence interval, 2.82-14.69) in naive but not in experienced individuals, but had no significant effect on survival. No significant effect of age was observed for MCMD. We conclude that in our cohort, HAART seems to alter the relationship between aging and HIVD, conferring a neuroprotective effect to older patients. These results may have significant implications for the clinical management of the older HIV population.

HIV encephalopathy has been in the past years the most typical CNS disorder in patients with AIDS. Histologic abnormalities consist in astrocytosis, myelin pallor, infiltration by infected macrophages, resident microglia and multinucleated giant cells, generally in absence of direct infection of neurons. Mononuclear phagocytes in the brain are the main target of HIV-1 infection and the site of productive viral replication, and viral stimulation leads to the release of neurotoxic products causing neurologic damage. Subclinical cardiac abnormalities are common in HIV+ patients and several studies suggested a role for cytokines and other inflammatory products as mediators of cardiac abnormalities. The common pathway for neurologic and cardiac manifestations supports the relationship between neurologic disease and cardiac dysfunction in HIV infection. Clinical observations suggest that cardiomyopathy could be associated with encephalopathy in HIV+ patients and that it may affect survival. Antiretroviral therapy may reduce impact of neurologic and cardiac abnormalities by suppressing plasma HIV-1 viral load.

To analyze the clinical efficacy of cidofovir combined with highly active anti-retroviral therapy (HAART) in AIDS-related progressive multifocal leukoen-cepalopathy (PML), a multicenter observational study was performed. Consecutive HIV-positive patients with histologically or virologically proven PML and at least 4 weeks of treatment after diagnosis were examined: 27 patients were treated with HAART, whereas 16 patients were treated with HAART plus cidofovir 5 mg/kg intravenously per week for the first 2 weeks and every other week thereafter. JC virus DNA was quantified in cerebrospinal fluid (CSF) by PCR. Baseline virologic, immunologic, and clinical characteristics as well as HIV RNA and CD4 responses to HAART were homogeneous between the groups. The median follow-up was 132 weeks. In one case (6%), cidofovir was permanently discontinued because of severe proteinuria. One-year cumulative probability of survival was 0.61 with cidofovir and 0.29 without (log rank test P = 0.02). After adjusting for baseline CD4 counts, JC viral load in CSF, Karnofsky, and use of HAART prior to the onset of PML, the use of cidofovir was independently associated with a reduced risk of death (hazard ratio, 0.21, 95% confidence interval, 0.07–0.65; P = 0.005). A randomized study will definitively establish whether cidofovir confers significant advantage over HAART alone in AIDS-related PML.

Background. A challenge in tuberculosis (TB) research is to develop a new immunological test that can help distinguish, among subjects responsive to QuantiFERON TB Gold In tube (QFT-IT), those who are able to control Mtb replication (remote LTBI, recent infection and past TB) from those who cannot (active TB disease). IFN-γ; response to the Heparin-binding-hemagglutinin (HBHA) of Mtb has been associated with LTBI, but the cumbersome procedures of purifying the methylated and immunological active form of the protein from Mtb or M. bovis Bacillus Calmette et Guerin (BCG) have prevented its implementation in a diagnostic test. Therefore, the aim of the present study was to evaluate the IFN-γ response to methylated HBHA of Mtb produced in M. smegmatis (rHBHAms) in individuals at different stages of TB who scored positive to QFT-IT. Methodology/Principal Findings. 87 individuals at different stages of TB who scored positive to QFT-IT were selected. IFN-γ response to in vitro whole blood stimulation with rHBHAms was evaluated by short-term and long-term tests and detected by ELISA or flow cytometry. We demonstrated that the IFN-γ response to rHBHAms is mediated by CD4+ T-cells with an effector-memory phenotype. This response, evaluated by short-term-tests, is significantly lower in active TB than in remote LTBI (p = 0.0010) and past TB (p = 0.0152). These results were confirmed by long-term tests. The qualitative data confirmed that IFN-γ responses higher than the cut-off point identified by ROC analysis are associated with the status of non-active disease. Conclusions. In this study we show that the T-cell response to a recombinant and methylated HBHA of Mtb produced in M. smegmatis is useful to discriminate between active and non-active TB disease among those responsive to QFT-IT in a whole blood system. Further studies are needed to improve the accuracy of the assay.

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.

Objective: To determine the effectiveness of antiretroviral therapy in controlling cerebrospinal fluid (CSF) HIV-1 replication and to assess factors related to virological response in advanced patients. Design: A cross-sectional and longitudinal study. Methods: Consecutive paired CSF and plasma samples from HIV-1-infected patients were collected before starting or changing highly active antiretroviral therapy (HAART). Results: In the cross-sectional analysis 75 patients were included, 55 (73%) with neurological disease, 28 (37%) naive for antiretroviral agents. A significant correlation between plasma and CSF levels at baseline was observed only in antiretroviral-experienced patients. The absence of neurological disease, lower plasma HIV-1 load and a previous exposure to indinavir were all associated with a baseline CSF HIV-1-RNA level less than 80 copies/ml at multivariate analysis. In 29 patients included in the longitudinal study a significant reduction in CSF HIV-1 RNA was observed. Plasma HIV-1-RNA change, CSF HIV-1-RNA level at baseline, overall months of antiretroviral treatment and the magnitude of difference between plasma and CSF HIV-1-RNA levels were all correlated to CSF HIV-1-RNA change during treatment. A significant difference in the magnitude of CSF HIV-1-RNA reduction was observed according to naive status and to the use of three or more drugs penetrating the blood-brain barrier. Conclusion: HAART effectively reduces HIV-1 replication in CSF. A variable response to antiretroviral therapy was observed in CSF, reflecting a different compartmentalization of infection during treatment. Naive status and the use of CNS-penetrating drugs substantially enhance antiviral response. A negative interaction between virological response and the duration of antiretroviral treatment suggests long-term selection of drug-resistant CSF HIV-1 strains.

Whereas most AIDS-related neurologic disorders have reduced incidence since HAART therapy was introduced, we find that the incidence of progressive multifocal leukoencephalopathy (PML) did not significantly differ between the pre-HAART and the HAART period (OR 0.78; 95% CI 0.41–1.50). These findings were confirmed by the preliminary results of the Italian Register Investigative Neuro AIDS (IRINA) Study, a prospective multicenter study started in January 2000, which showed that PML was the second most frequently diagnosed neurologic disorder after TE. A similar proportion of cases were found in HAART-naove and HAART-experienced patients in our experience. PML was more common in the presence of HIV RNA > 500 copies/ml. Most of the cases occurring in HAART-exposed patients developed within the first 6 months of therapy. As others have reported, we find a prolonged survival in PML subjects prescribed HAART (245 days in the group treated with HAART versus 66 days in the group not treated with HAART; P at log rank = 0.001). However despite the survival benefit, AIDS-associated PML still has a serious prognosis. In fact, PML had the lowest 1-year survival probability of any cerebral disorder in our study (P = 0.0005). Our findings also confirm that CSF JCV DNA burden at baseline is a useful prognostic indicator with a threshold of 4.7 log10 JCV copies/ml (P at log rank = 0.01) in our experience. CSF JCV DNA load at 4 weeks of follow-up and clearance of JCV-DNA from CSF are associated with a better neurologic outcome and a longer survival.

A multicenter analysis of 57 consecutive human immunodeficiency virus-positive patients with progressive multifocal leukoencephalopathy (PML) was performed, to identify correlates of longer survival. JC virus (JCV) DNA was quantified in the cerebrospinal fluid (CSF) by polymerase chain reaction. Two months after therapy, 4% of the patients without highly active antiretroviral therapy (HAART) and 26% with HAART showed neurologic improvement or stability (P=.03), and 8% and 57%, respectively, reached undetectable JCV DNA levels in the CSF (P=.04). One-year probability of survival was.04 without HAART and.46 with HAART. HAART and lack of neurologic progression 2 months after diagnosis were independently associated with longer survival. Among HAART-treated patients, a baseline JCV DNA

Objectives: To analyse the virological and clinical efficacy of cidofovir combined with highly active antiretroviral therapy (HAART) in AIDS-related progressive multifocal leukoencephalopathy (PML). Design: Multicentre observational study of consecutive HIV-positive patients with histologically or virologically-proven PML. Group A, 26 patients treated with HAART; group B, 14 patients treated with HAART plus cidofovir 5 mg/kg intravenously per week for the first 2 weeks and alternate weeks thereafter. JC virus DNA was quantified in cerebrospinal fluid (CSF) by PCR. Results: Baseline virological, immunological and clinical characteristics were homogeneous between the groups. In one case cidofovir was discontinued because of severe proteinuria. There was no significant difference in HIV RNA responses and changes in the number of CD4 cells between group A and B. After 2 months of therapy, five out of 12 (42%) patients from group A and seven out of eight (87%) from group B reached undetectable JC virus DNA in the CSF (Chi-square P= 0.04); moreover, 24% of group A and 57% of group B patients showed neurological improvement or stability (P= 0.038). One-year cumulative probability of survival was 0.67 with cidofovir and 0.31 without (log-rank test, P = 0.01). Variables independently associated with longer survival were the use of cidofovir, HAART prior to the onset of PML, a baseline JC virus DNA load in CSF < 4.7 log 10 copies/ml, and a baseline Karnofsky performance status ≥ 60. Conclusions: In AIDS-related PML, cidofovir added to HAART is associated with a more effective control of JCV replication, with improved neurological outcome and survival compared with HAART alone.

Background Reactivation of occult or inactive Hepatitis B virus (HBV) infection during immunosuppressant treatments is well known and widely described in literature. The same observation has been made in Hepatitis C (HCV)-infected patients previously exposed to HBV and treated with interferon-free DAA treatments. Because of common transmission routes, persons may have been exposed to HCV, HBV and HIV, but few cases have been reported in this scenario to date. Frequency of HBV reactivation in HIV/HCV co-infected patients previously exposed to HBV and treated with DAA remains unclear. Herein, we report an episode of HBV reactivation in an HIV/HCV co-infected patient prescribed with sofosbuvir/ledipasvir for HCV. Case presentation The patient is a Caucasian 54-years old female, with HIV/HCV co-infection (genotype 4), and a previous exposure to HBV, documented by negativity of HBsAg and positivity of HBsAb and HBcAb. Her medical history included: myocardial infarct, chronic kidney disease stage 3, chronic obstructive pulmonary disease, and mild pulmonary hypertension. HCV had not been treated with interferon (IFN)-based regimens and liver stiffness was 10.5 KPa (Metavir stage F3) at hepatic elastography. Because of CKD, she was prescribed with a nucleoside reverse transcriptase (NRTI)-sparing regimen including darunavir/ritonavir plus etravirine, and thereafter with sofosbuvir/ledipasvir for 12 weeks. Four weeks after DAA termination, the patient was hospitalized with symptoms of acute hepatitis. Blood tests showed HCV RNA