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Ribavirin is an inosine monophosphate dehydrogenase inhibitor with demonstrated activity against coronaviruses, including SARS-CoV-2. Five hospitalized patients with COVID-19 (confirmed by positive tests for SARS-CoV-2) received treatment with ribavirin for inhalation solution (ribavirin aerosol) as part of a compassionate use program. Patients included four men and one woman, with an age range of 29–72years. Patients were managed according to international and Italian treatment guidelines for COVID-19. In addition, therapy with ribavirin aerosol 100mg/mL was administered for 30min twice daily for 6days (i.e., 12 doses) in all patients. In order to address concerns about a possible increase in viral dispersal with the use of a nebulizer, healthcare providers remained outside the patient room during ribavirin aerosol administration. Pretreatment chest computed tomography (CT) scans showed pseudonodular areas of parenchymal thickening in the upper right lobe with associated ground glass opacities, multiple areas of parenchymal consolidation in both lower lobes with associated ground glass opacities, bilateral parenchymal thickening and multiple associated ground glass areas, or focal ground glass areas in the upper lobes bilaterally, which were almost completely resolved (three patients) or moderately cleared (one patient) on imaging at the end of ribavirin treatment. For a fifth patient, CT scans showed a stable pulmonary picture at the end of ribavirin treatment. No adverse reactions to ribavirin treatment were observed in any of the five patients. All patients recovered fully, and nasopharyngeal swabs obtained after hospital discharge tested negative for SARS-CoV-2. Ribavirin aerosol appears to be efficacious in the treatment of patients with COVID-19. A controlled trial of ribavirin aerosol is ongoing and will provide additional data across a broader patient population.

Objectives The aim of our study was to describe the incidence and predictive factors of secondary infections in patients with coronavirus disease 2019 (COVID-19). Methods This was a cohort study of patients hospitalized with COVID-19 at IRCCS San Raffaele Hospital between 25th February and 6th April 2020 (NCT04318366). We considered secondary bloodstream infections (BSIs) or possible lower respiratory tract infections (pLRTIs) occurring 48 hours after hospital admission until death or discharge. We calculated multivariable Fine–Gray models to assess factors associated with risk of secondary infections. Results Among 731 patients, a secondary infection was diagnosed in 68 patients (9.3%); 58/731 patients (7.9%) had at least one BSI and 22/731 patients (3.0%) at least one pLRTI. The overall 28-day cumulative incidence was 16.4% (95%CI 12.4–21.0%). Most of the BSIs were due to Gram-positive pathogens (76/106 isolates, 71.7%), specifically coagulase-negative staphylococci (53/76, 69.7%), while among Gram-negatives (23/106, 21.7%) Acinetobacter baumanii (7/23, 30.4%) and Escherichia coli (5/23, 21.7%) predominated. pLRTIs were caused mainly by Gram-negative pathogens (14/26, 53.8%). Eleven patients were diagnosed with putative invasive aspergillosis. At multivariable analysis, factors associated with secondary infections were low baseline lymphocyte count (≤0.7 versus >0.7 per 109/L, subdistribution hazard ratios (sdHRs) 1.93, 95%CI 1.11–3.35), baseline PaO2/FiO2 (per 100 points lower: sdHRs 1.56, 95%CI 1.21–2.04), and intensive-care unit (ICU) admission in the first 48 hours (sdHR 2.51, 95%CI 1.04–6.05). Conclusions Patients hospitalized with COVID-19 had a high incidence of secondary infections. At multivariable analysis, early need for ICU, respiratory failure, and severe lymphopenia were identified as risk factors for secondary infections.

Background:Very limited data are available on the immunovirological outcomes after 13-valent pneumococcal conjugate vaccine (PCV13) in antiretroviral therapy (ART)-treated patients. The aim of this study was to assess the immune-virological outcomes in HIV-1-infected ART-treated patients on stable virological suppression who underwent pneumococcal conjugate vaccination.Methods:Retrospective, cohort study on ART-treated HIV-1-infected individuals, age at least 18 years, with three consecutive determinations of HIV-RNA less than 50 copies/ml before the administration of PCV13 (baseline) at San Raffaele Hospital and with at least two HIV-RNA values after vaccination.Results:Overall 1197 patients underwent PCV13 vaccination. During 6-month of follow-up (594 person-years of follow-up, PYFU), 12 confirmed virological failure and 35 viral blips were observed; the overall incidence rate of confirmed virological failure was 2.02 (95% confidence interval: 0.88-3.16) per 100-PYFU and the incidence rate of viral blips was 5.89 (95% confidence interval: 3.94-7.84) per 100-PYFU. Median CD4+ cell count change from baseline at 6 months was +10 cells/μl (interquartile range -67, +111; P = 0.0002). Median change in CD4+/CD8+ ratio was +0.02 (interquartile range -0.06, +0.11; P < 0.001).Conclusion:Viral blips and confirmed virological failures were rarely observed in patients on stable virological suppression in the first 6 months following vaccination with PCV13. In addition, no decrease of CD4+ cell count and CD4+/CD8+ ratio was recorded.

To the Editor,Updated recommendations on antiretroviral treatment for HIV infection were recently published by the present journal [1]. In line with international guidelines [2], a combination of t...

Objectives The aim of the study was to assess whether pill burden is associated with self-reported adherence to current combination antiretroviral regimens and health status in a large sample of unselected and chronically treated HIV-infected patients. Methods An adherence and health status questionnaire was offered to all patients collecting their drugs between March and May 2010 at our clinic; both parameters were primarily evaluated using a visual analogue scale. Linear correlations were evaluated using Spearman's correlation coefficient. Wilcoxon's rank-sum test and the χ2 test were used to compare quantitative and qualitative variables. The generalized linear model was used in multivariable analyses. Results Among 2763 subjects on treatment during the study period, 2114 (78.8% male; mean age 46.9 ± 8.84 years) were tested for adherence; 1803 (85.3%) had viral loads

The objective of this study was to investigate the mechanisms underlying the virological and immunological changes occurring in failing HIV-1 infected patients undergoing treatment interruption or lamivudine monotherapy (the E-184V Study). Associations were sought between the de-selection of individual reverse transcriptase and protease resistance mutations and replication capacity recovery, HIV-RNA changes, and immunological changes. The replication capacity recovery was defined as the ratio between the replication capacity at weeks 24 or 48, and that measured at baseline. The replication capacity recovery, which was evaluable in 21 patients at week 24 and in 18 at week 48, was significantly higher in the treatment interruption than in the lamivudine group at week 24 (P = 0.002). Forty-eight week replication capacity recovery was greater when the 184V (P = 0.023), the 41L (P = 0.02), or the 215Y mutation (P = 0.037) were deselected at week 12. A greater reduction in the CD4+/CD8+ ratio at week 48 (P = 0.038) was observed as the 184V mutation was deselected and the de-selection of the 184V mutation at week 12 was the only independent predictor of the change of the CD4+/CD8+ ratio at week 48 from baseline at multivariable analysis (F-value = 6.72, P = 0.021). In conclusion, among patients undergoing treatment interruption or lamivudine monotherapy, the recovery of HIV-1 replication capacity was associated with the de-selection of reverse transcriptase mutations. The de-selection of the 184V mutation predicts independently a reduction in the CD4+/CD8+ ratio.

Objectives To characterize osteoprotegerin (OPG) levels, bone remodelling and bone mineral density (BMD) in heavily pretreated HIV-infected patients on antiretroviral therapy, and to evaluate the clinical factors associated with bone density decline. Methods Heavily pretreated (>5 years) HIV-positive patients were enrolled in this cross-sectional, observational study, which was based on a total body bone densitometry examination and a comprehensive evaluation of bone and mineral parameters. Results Sixty-eight patients (55 male and 13 female) with a median age of 41 years (range 25–60 years) were included in the study. Their antiretroviral treatment lasted for 82 months. On the basis of the World Health Organization criteria, nine patients (13.2%) were osteoporotic [T-score

Many studies have demonstrated that the long-term, virological, immunological and clinical effectiveness of highly active antiretroviral therapy (HAART) is mainly related to durable suppression of viral replication. Among the specific antiretroviral agents available today, nelfinavir has been widely used in the last 3 years. This open label, non comparative, retrospective study on 307 patients living with HIV aimed to evaluate the effectiveness of an antiretroviral (ART) regimen including nelfinavir as first-line HAART in terms of rate and durability of viro-immunological response. Most patients, 258/307 (84%), were pre-treated whereas only 49/307 (16%) were treatment naive. The median baseline CD4 cell count was 223 cells/mm(3) for naive patients and 317 cells/mm(3) for experienced patients whereas median HIV RNA values were 2,500 and 82,000 copies/ml for experienced and naive patients respectively. Median times spent on nelfinavir were 839 and 897 days for experienced and naive patients respectively, with 171/258 pre-treated patients (66%) remaining on nelfinavir-based therapy up to 24 months. Overall, the mean CD4 increase was 196 cells/mm(3) with a relevant increment of 165 in experienced patients and 367 cells/mm3 in naive patients (p

Genotypes in nine highly protease inhibitor (PI)-experienced patients were studied before and after lopinavir/ritonavir (LPV/r) treatment. Resistance to amprenavir was the rule both before and after LPV/r treatment. Treatment with LPV/r can select for the 50 V mutation. In this setting, significant differences in the inference of the amprenavir phenotype from genotype were observed when using different algorithms.

Objective: To evaluate the 24-week effects on glucose tolerance of switching from a protease inhibitor (PI)-based to an unboosted atazanavir-including regimen in highly pretreated HIV-1 infected subjects with metabolic alterations. Design: Prospective, open-label, single-center, 24-week pilot study. Methods: Twenty-one subjects underwent an oral glucose tolerance test (OGTT) at baseline (BL) and after 24 weeks of unboosted atazanavir. Insulin sensitivity and β-cell responsiveness were evaluated on the basis of static and dynamic data; fasting glucose, insulin, C-peptide, triglycerides (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), TC/HDL-c ratio, CD4+ cell count and HIV-1 RNA were measured. Results: After 24 weeks of unboosted atazanavir, the 120-min glucose level was significantly lower than the one measured at BL (P=0.021); there were no statistically significant differences in the insulin concentration profile. The SIoral, an OGTT-based index of insulin sensitivity, was significantly higher at week 24 (P=0.017); the indices of first- and second-phase β-cell responsiveness did not significantly change. There was no significant difference between BL and 24-week fasting glucose, insulin or C-peptide levels, and consequently no change in fasting homeostasis model assessment indices of insulin sensitivity and β-cell function. There were significant improvements in TG (P=0.009), TC (P=0.0001), LDL-c (P=0.019) and TC/HDL-c ratio (P=0.001), and a similar trend in HDL-c levels (P=0.069). No significant changes in the immunological and virological parameters were detected. Conclusions: Our results show that switching from a PI-based to an unboosted atazanavir-including regimen leads to a significant improvement in glucose tolerance in highly pretreated HIV-1 infected subjects with metabolic alterations.

Patients infected with HIV-1 with more than 1000 HIV-1 RNA copies/mL, who were genotyped within 3 months before starting stavudine and treated for at least 3 months with a stable stavudine-containing highly active antiretroviral therapy, were selected from our database to identify the determinants of response to stavudine. Nonresponsewas defined as a failure to achieve HIV-1 RNA level of less than 400 copies/mL or a reduction of more than 2 log(10) by week 12. Univariate logistic analysis was used to elicit the failure-associated reverse transcriptase mutations (scored I to develop a genotype score). Eighty-one patients were eligible for the analysis, including 75 (93%) who previously received zidovudine. Thirty-five (43%) were nonresponders. Univariate logistic analysis revealed the following failure-associated mutations: 41 L (P = 0.0001), 44D (P = 0.02), 1181 (P = 0.0006), 184V (P = 0.04), 210W (P = 0.0004), and 215Y (P = 0.002) for a median stavudine score of 2. Failure was observed in 7 (18.9%) of 37 patients with a score less than 2, compared with 28 (63.6%) of 44 patients with a score of 2 or greater (P < 0.0001). The multivariable analysis showed that the 1181 mutation (P = 0.04) was the only independent genotypic predictor of failing on a stavudine-containing highly active antiretroviral therapy.

The genotypic inhibitory quotient (GIQ) is the ratio between drug concentration and the number of resistance mutations. However, as different resistance scores can be calculated for the same protease inhibitor, the ability of a GIQ to predict the virological outcome may vary depending on the resistance score used as the denominator. Forty-four highly treatment-experienced HIV-infected patients failing on their current regimen were treated with a lopinavir/ritonavir-containing combination for at least 48 weeks. Three GIQs were calculated for each patient: the denominator of the first (GIQ-A) was the lopinavir/ritonavir score calculated using the mutations listed by IAS-USA as being related to lopinavir/ritonavir resistance; the denominator of the second (GIQ-B) was the total number of mutations related to resistance to any protease inhibitor as reported by IAS-USA; and the denominator of the third (GIQ-C) was the lopinavir/ritonavir score proposed by Parkin et al. The median (IQR) of the GIQ-A, B, and C was 4.69 (3.83-9.76), 0.97 (0.74-1.62), and 1.02 (0.68-2.52), respectively. At week 48, the median decrease in HIV-RNA was 1.09 (0.32-2.34) log(10) copies/ml (P < 0.0001), with 13 subjects (29.5%) attaining undetectable levels. All of the GIQs independently predicted the change in viral load from baseline and undetectable HIV-RNA at week 48. The partial R(2) of GIQ-C was greater than that of GIQ-B, which was greater than that of GIQ-A. All of the GIQs were independent predictors of the 48-week virological response. The predictive value of the GIQ for lopinavir/ritonavir may vary depending on the algorithm used to score drug resistance.

Objective: We compared the immunological and clinical outcomes of lamivudine monotherapy and complete therapy interruption in the treatment of HIV-1-infected patients harbouring lamivudine-resistant virus. Methods: This 48-week, open-label pilot study randomly assigned HIV-infected patients receiving lamivudine-containing HAART and harbouring the M184V mutation to monotherapy with lamivudine 300 mg once daily (lamivudine group) or the discontinuation of all antiretroviral drugs (TI group). The primary endpoint was the occurrence of immunological or clinical failure; immunological failure was defined as the first report of a CD4 T-cell count less than 350 cells/mu l, and clinical failure as the occurrence of a Centers for Disease Control and Prevention grade B or C event. The data were analysed on the basis of the intention-to-treat principle. Results: By week 48,20 of 29 patients in the TI group (69%; 95% CI 51-83%) and 12 of 29 in the lamivudine group (41%; 95% CI 26-59%) had discontinued the study because of immunological or clinical failure, which was significantly delayed in the lamivudine group (P=0.018). Only patients in the TI group (6/29, 20.7%) experienced grade 3-4 clinical adverse events at least possibly related to HIV-1 (P=0.02). The mean decline in CD4 cell percentage, viral rebound and recovery of HIV-1 replication capacity were significantly lower in the lamivudine group. The 24-week virological and immunological response after therapy resumption in patients who prematurely discontinued the study was similar in the two groups. Conclusion: In HIV-1-infected patients harbouring a lamivudine-resistant virus, lamivudine monotherapy may lead to a better immunological and clinical outcome than complete therapy interruption. (C) 2006 Lippincott Williams & Wilkins.

The redistribution of mutations related to protease inhibitor (PI) resistance after a PI-sparing regimen in human immunodeficiency virus (HIV)-infected, highly PI-experienced patients was prospectively assessed. Twenty-five patients failing a PI-including regimen were given PI-sparing antiretroviral therapy, and then followed for 24 weeks after PI resumption. Genotyping was performed by direct sequencing before and during the PI-sparing regimen. The median (interquartile range, IQR) baseline CD4+ T-lymphocyte count was 198 (120-255) cells/microl, and the median HIV-RNA level was 82,000 (41,000-300,000) copies/ml. Patients had experienced a median of 4.5 (4-5.25) PIs. The median number of PI mutations was eight (6-9). The PI-sparing regimen consisted of a median of three (3-4) drugs and lasted for a median of 53 (24-67) weeks. At the end of the study, the median number of PI mutations was 6.5 (6-9). The median change in the number of PI mutations was -1 (IQR from -1 to 0). A reduction from baseline was observed in 13 cases (52%); nine (36%) showed no change and three (12%) showed an increased number of PI substitutions. In highly PI-experienced patients, a PI-sparing regimen may lead to a reduction, no change, or increase in the number of PI mutations. The reduction is negligible in most cases.

Objectives: The aim of this study was to evaluate the correlation between liver function markers (necrosis and cholestasis) and plasma lopinavir levels in a cohort of HIV-infected patients treated with lopinavir and ritonavir. Patients and methods: The blood samples for determining steady-state C-trough lopinavir levels and analysing liver function were drawn from fasting patients. Steady-state C-trough lopinavir levels, liver function and immuno-virological markers were assessed on the same day. Plasma lopinavir and ritonavir levels were determined by means of high-performance liquid chromatography. Results: One hundred and forty-nine patients were included in the analysis [57 were HCV co-infected (34%) and 10 were HBV co-infected (6.7%)]; they had been treated with lopinavir/ritonavir for a median of 232 days (range 132-282). All patients received lopinavir/ritonavir [400/100 mg twice daily or 533/133 mg twice daily if amprenavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI) was part of therapy] and concomitant therapy with NRTI(s). Median (interquartile) lopinavir trough levels were 6391 ng/mL (4121-8726), 5662 (3585-8893) and 6819 ng/mL (5324-8726) in the patients with HIV alone and those with HIV/HCV (or HBV) co-infection, respectively (P = not significant). Univariate analysis showed a significant association between the cholestasis markers and C-trough lopinavir level. Multivariate analysis selected only gamma glutamyltranspeptidase (GGT) (OR = 1.010, 95% CI: 1.002-1.021) as being independently associated with plasma lopinavir levels of > 6425 ng/mL; alkaline phosphatase (OR = 1.004, 95% CI: 1.000-1.010; P = 0.08) and total bilirubin (OR = 3.118, 95% CI: 0.980-11.715; P = 0.07) were not associated. Conclusions: Elevated lopinavir concentrations are associated with raised GGT.

The human immunodeficiency virus type 1 (HIV-1) fusion inhibitor enfuvirtide has recently been introduced into clinical practice and has exhibited efficient anti-HIV-1 activity in combination with other antiretroviral agents. In the present study, we addressed the effect of long-term treatment with enfuvirtide on the intrahost evolution of HIV-1. The genotype and phenotype patterns and the relative replication capacity (rRC) of enfuvirtide-resistant HIV-1 mutants were evaluated in samples from 11 subjects (7 virological nonresponders and 4 responders) who received the compound for more than 1 year in combination with different regimens. Selection of one or more mutations clustering in a sequence (amino acids 36 to 45) of the gp41 N-terminal heptad repeat was observed in samples from the seven virological nonresponders but not in those from responders. In two subjects who discontinued enfuvirtide, reversion of the resistant genotype was detected within 3 months. Recombinant clones bearing mutated gp41 sequences displayed reduced susceptibilities to enfuvirtide, with the 50% inhibitory concentrations (IC 50 s) ranging from 0.6 to 12.8 μg/ml, whereas the IC 50 for isolates with baseline sequences was 0.013 ± 0.010 μg/ml. Interestingly, long-term monitoring of resistant variants provided evidence that ongoing adaptation to the drug is paralleled by phenotypic changes. A limited drop in the rRC in the absence of drug was observed for clones from four of the seven nonresponders bearing mutations associated with resistance. Overall, the data indicate that the different genotype patterns associated with a detectable degree of HIV-1 resistance to enfuvirtide generated during long-term treatments are characterized by a substantially low genetic barrier, possible ongoing adaptation with increased degrees of resistance, and limited influence on the viral rRC.

We performed polymerase chain reaction (PCR) for detection of cytomegalovirus (CMV), varicella-zoster virus (VZV), herpes simplex virus (HSV), and Toxoplasma gondii DNA in aqueous humor from 15 patients who were infected with human immunodeficiency virus (HIV) and who had retinitis of unclear origin; these patients were selected from among 820 patients evaluated by ophthalmoscopic examination. On the basis of the final response to treatment, CMV, VZV, and T. gondii retinitis was diagnosed in 5, 2, and 4 of the 15 patients, respectively, No final etiologic diagnosis was reached for four patients. All 5 patients with CMV retinitis were CMV DNA-positive, 1 of 2 patients with VZV retinopathy were VZV DNA-positive, and 3 of 4 patients with T. gondii retinitis were T. gondii DNA-positive. All PCR assays of aqueous humor from the four patients without infectious retinitis were negative. PCR assay of aqueous humor is helpful in the etiologic diagnosis of retinitis of unclear origin in HIV-infected patients.

Objective To investigate the normalized inhibitory quotient (NIQ) of lopinavir (LPV) as a predictor of 48-week virological responses to a lopinavir/ritonavir (LPV/RTV)-containing regimen in highly treatment-experienced patients. Design We calculated the NIQ for 59 patients who completed 48 weeks’ treatment and assessed the factors predicting a week-48 virological response. Methods The NIQ was calculated by dividing each subject's IQ (LPV Ctrough/fold change in LPV susceptibility, as assessed by VirtualPhenotype™) by a reference IQ (mean population LPV Ctrough/fold change in LPV IC50, as assessed by VirtualPhenotype™). HIV-1 RNA was assessed by NASBA (quantification limit: 80 copies/ml). The general linear model and multiple logistic regression, respectively, were used to estimate the independent predictors of a change in viral load and HIV-1 RNA Results The median (interquartile range) baseline levels of CD4+ cells and HIV-1 RNA were 251 (141–385) cells/μl and 4.85 (4.49–5.23) log10 copies/ml, respectively. The median NIQ was 2.2 (0.5–14). At week 48, the median decrease in HIV-1 RNA was 1.4 (0.59–2.79) log10 copies/ml ( PConclusion The LPV NIQ independently predicts virological responses to an LPV/RTV-containing regimen in highly treatment-experienced HIV-1-infected patients.