Correction: Cruciani et al. Ivermectin for Prophylaxis and Treatment of COVID-19: A Systematic Review and Meta-Analysis. Diagnostics 2021, 11, 1645.

The correct affiliation 1 should be "Italian National Blood Centre, National Institute of Health, 00162 Rome, Italy" [...].

Ivermectin for Prophylaxis and Treatment of COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Ivermectin has received particular attention as a potential treatment for COVID-19. However, the evidence to support its clinical efficacy is controversial. OBJECTIVES: We undertook a new systematic review of ivermectin for the treatment and prophylaxis of COVID-19, including new primary studies, outcomes other than mortality, and grading the quality of the available evidence following the Cochrane guidance for methodology. METHODS: We searched electronic databases, repository databases, and clinical trial registries (up to June 2021). The measure of treatment effect was risk difference (RD) with 95% confidence intervals (CIs). The GRADE system was used to assess the certainty of the evidence. RESULTS: The review includes 11 RCTs (2436 participants). The certainty of the available evidence was quite low or very low due to risk of bias, inconsistency, and imprecision. When the analysis was limited to patients with baseline mild or moderate disease (8 reports, 1283 patients), there were no differences in mortality between ivermectin and control groups (low level of certainty); in patients with baseline severe diseases (3 reports, 304 patients), the use of ivermectin significantly decreased mortality compared to the controls (RD -0.17; 95% CIs, -0.24/-0.10; p = 0.00001; low level of certainty). In terms of disease progression (to severe pneumonia, admission to intensive care unit, and/or mechanical ventilation), the results were much the same. At day 14, the rate of patients with a negative RT-PCR test was 21% higher (from 5 to 36% higher) for ivermectin recipients than it was for the controls (low quality of evidence). Three studies (736 subjects) indicated that prophylaxis with ivermectin increased the likelihood of preventing COVID-19 compared to controls (low quality of evidence). Serious adverse events were rarely reported. CONCLUSIONS: There is limited evidence for the benefit of ivermectin for COVID-19 treatment and prophylaxis, and most of this evidence is of low quality. Further evidence is needed to fine-tune potential indications and optimal treatment protocols for ivermectin as a treatment for COVID-19.

Susceptibility to HIV-1 integrase strand transfer inhibitors (INSTIs) in highly treatment-experienced patients who failed an INSTI-based regimen.

The aim of this study was to characterize the genotypic and phenotypic resistance profile to the integrase strand transfer inhibitor (INSTI) bictegravir (BIC) and other INSTIs in patients who previously failed twice-daily raltegravir (RAL)-based or twice-daily dolutegravir (DTG)-based regimens. Twenty-two samples were collected after failure on an INSTI-based regimen in 17 highly treatment-experienced patients with HIV-1 with multi-drug-resistant virus, recorded in the Italian PRESTIGIO registry. Genotypic resistance mutations and phenotypic susceptibility to INSTIs were detected by GeneSeqIN and PhenoSenseIN assays, respectively (Monogram Biosciences, San Francisco, CA, USA). The primary INSTI resistance substitutions E138A/K, G140S, Y143C/H/R, Q148H and N155H were detected in 14 of 22 samples and were associated with resistance to one or more INSTIs, with G140S+Q148H present in 11 of 22 samples. Of these 14 samples, all showed high levels of resistance to elvitegravir (EVG) and RAL. Two isolates contained L74M, E138K, G140S and Q148H, or L74M, T97A, S119T, E138K, G140S, Y143R and Q148H, and had high-level resistance to all INSTIs, including BIC and DTG. Intermediate resistance was reported for eight of 14 isolates for BIC and nine of 14 isolates for DTG. Overall, for the 14 INSTI-resistant isolates, the median fold-change values in phenotypic susceptibility were: BIC 3.2 [interquartile range (IQR) 0.6-66], DTG 6.3 (IQR 0.8->186), EVG >164 (IQR 2.6->164) and RAL >188 (IQR 2.7->197). In conclusion, the study findings supported the in-vitro activity of BIC and DTG against most isolates derived from highly treatment-experienced patients who failed INSTI regimens.

HIV-1-Associated Neurocognitive Disorders: Is HLA-C Binding Stability to ß2-Microglobulin a Missing Piece of the Pathogenetic Puzzle?

AIDS dementia complex (ADC) and HIV-associated neurocognitive disorders (HAND) are complications of HIV-1 infection. Viral infections are risk factors for the development of neurodegenerative disorders. Aging is associated with low-grade inflammation in the brain, i.e., the inflammaging. The molecular mechanisms linking immunosenescence, inflammaging and the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, are largely unknown. ADC and HAND share some pathological features with AD and may offer some hints on the relationship between viral infections, neuroinflammation, and neurodegeneration. ß2-microglobulin (ß2m) is an important pro-aging factor that interferes with neurogenesis and worsens cognitive functions. Several studies published in the 80-90s reported high levels of ß2m in the cerebrospinal fluid of patients with ADC. High levels of ß2m have also been detected in AD. Inflammatory diseases in elderly people are associated with polymorphisms of the MHC-I locus encoding HLA molecules that, by associating with ß2m, contribute to cellular immunity. We recently reported that HLA-C, no longer associated with ß2m, is incorporated into HIV-1 virions, determining an increase in viral infectivity. We also documented the presence of HLA-C variants more or less stably linked to ß2m. These observations led us to hypothesize that some variants of HLA-C, in the presence of viral infections, could determine a greater release and accumulation of ß2m, which in turn, may be involved in triggering and/or sustaining neuroinflammation. ADC is the most severe form of HAND. To explore the role of HLA-C in ADC pathogenesis, we analyzed the frequency of HLA-C variants with unstable binding to ß2m in a group of patients with ADC. We found a higher frequency of unstable HLA-C alleles in ADC patients, and none of them was harboring stable HLA-C alleles in homozygosis. Our data suggest that the role of HLA-C variants in ADC/HAND pathogenesis deserves further studies. If confirmed in a larger number of samples, this finding may have practical implication for a personalized medicine approach and for developing new therapies to prevent HAND. The exploration of HLA-C variants as risk factors for AD and other neurodegenerative disorders may be a promising field of study.

Combination dolutegravir-abacavir-lamivudine in the management of HIV/AIDS: clinical utility and patient considerations.

The current standard of care for human immunodeficiency virus (HIV) treatment is a three-drug regimen containing a nonnucleoside reverse transcriptase inhibitor, a protease inhibitor, or an integrase strand transfer inhibitor (INSTI) plus two nucleoside/tide reverse transcriptase inhibitors. Given their potency, safety, and distinctive mechanism of action, INSTIs represent an important advance in HIV type 1 (HIV-1) therapy. Dolutegravir (DTG) is a new-generation INSTI recently approved for the treatment of HIV-1-infected adult patients, with distinct advantages compared with other available antiretroviral agents. In well-designed, large clinical trials, DTG-containing regimens have demonstrated either noninferiority or superiority to current first-line agents such as raltegravir-, darunavir/ritonavir-, and efavirenz-containing regimens. The favorable safety profile, low potential for drug interactions, minimal impact on lipids, good tolerability, and high resistance barrier of DTG makes this compound one of the preferred choices for HIV therapy in multiple clinical scenarios, including treatment-naïve and treatment-experienced patients. DTG is the only antiretroviral drug not yet associated with de novo emergence of resistance mutations in treatment-naïve individuals. However, data from in vitro studies and clinical trial suggest the possibility of cross-resistance between first- and second-generation INSTIs. Even though these profiles are infrequent at the moment, they need to be monitored in all current patients treated with INSTIs. With its potent activity, good tolerability, simplicity of dosing, and minimal drug interaction profile, DTG will likely play a major role in the management of patients with HIV-1 infection. On the basis of clinical trial data, current guidelines endorse DTG in combination with nucleoside/tide reverse transcriptase inhibitors as one of the recommended regimens in antiretroviral therapy-naïve patients. Most of the favorable clinical experiences from clinical trials are based on the combination of DTG with abacavir/lamivudine, and DTG is planned to be coformulated with abacavir/lamivudine. This will provide a further advantage, given that single tablet regimens are associated with higher adherence rates as well as improvement in quality of life and enhanced patient preference.

Virological efficacy of abacavir: systematic review and meta-analysis.

OBJECTIVES: The efficacy of abacavir/lamivudine has been reported to be inferior to tenofovir/emtricitabine. Several randomized clinical trials (RCTs) investigated the effectiveness and safety of abacavir/lamivudine and tenofovir/emtricitabine combined antiretroviral treatment (cART) and we have reviewed the available evidence. DESIGN: Systematic review and meta-analysis of RCTs using standard Cochrane Collaboration methodologies. METHODS: We calculated risk ratios (RRs) with 95% CIs. The primary outcome was the rate of patients with viral load (VL) below the pre-defined cut-off at 48 weeks and/or at 96 weeks. Where available, results were analysed according to VL screening levels (<100,000 or >100,000 copies/mL) with conventional meta-analytical pooling by subgroups and meta-regression. RESULTS: Meta-analytical pooling of RCTs with a direct comparison of abacavir/lamivudine and tenofovir/emtricitabine according to baseline VL at 48 weeks (six trials, 4118 patients) showed that the proportions of subjects with VL <50 copies/mL were similar in the overall comparison (RR 0.98; 95% CI 0.94-1.03), in the low baseline VL strata (RR 1.01; 95% CI 0.99-1.03) and in the high baseline VL strata (RR 0.96; 95% CI 0.90-1.03). Meta-regression analysis at 48 weeks confirms the results of subgroup analysis. Similar virological results were found at 96 weeks (four trials, 2003 patients). Differences in the occurrence of adverse events requiring discontinuation of treatment favoured tenofovir recipients (RR 1.26; 95% CI 0.99-1.61), but this difference, mostly related to suspected abacavir hypersensitivity reaction, was not statistically significant. CONCLUSIONS: Our cumulative, cross-sectional data suggest a similar virological efficacy of abacavir/lamivudine and tenofovir/emtricitabine regardless of the baseline VL.

Abacavir-based triple nucleoside regimens for maintenance therapy in patients with HIV.

BACKGROUND: Regimen simplification can be defined as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirements. Many patients on suppressive antiretroviral therapy may be considered candidates for a simplification strategy and, among them, those who have achieved virologic suppression. Several clinical trials have evaluated the efficacy of triple nucleoside combination as a simplification therapy in patients who achieved virologic suppression OBJECTIVES: The aim of this review is to combine randomised, controlled trials to examine whether in patients with undetectable viraemia on a Protease inhibitor (PI) based regimen simplification treatment with abacavir (ABC)-based triple-nucleoside combinations has similar rates of efficacy and tolerability compared with a PI regimen or simplification with a NNRTIs (efavirenz-EFV- or nevirapine-NVP) containing regimen. Studies were included if they had at least two of the three interventions, including one 3NRTI arm. SEARCH METHODS: Electronic databases and conference proceedings were searched (1996-2012) with relevant search terms without limits to language. SELECTION CRITERIA: Randomised controlled trials (RCTs) only are included in this review. Patients population is represented by HIV-infected adult patients treated with a PI-containing regimen (PI or boosted PI),  with undetectable viral load. Patients on a PI-containing regimen had three possibilities: continue the PI regimen or switch to a simplification maintenance regimen, including switch to a NNRTI (EFV or NVP) containing regimen, or switch to a triple-NRTI regimen (ABC-zidovudine-lamivudine) DATA COLLECTION AND ANALYSIS: The primary outcomes were: proportion of patients discontinuing or switching antiretroviral therapy due to virologic failure or to adverse events; death (all cause) and AIDS defining illness; occurrence of myocardial infarction and cardiovascular disease. Secondary outcomes  were: proportion of patients maintaining an undetectable viral load (e.g. HIV-RNA <50 or <400 copies/mm(3)); change in mean CD4+ cell count; occurrence of lipodystrophy. We applied Cochrane Collaboration tools to assess each individual study for risk for bias. MAIN RESULTS: We included eight RCT, for a total of 1,610 patients. All the studies included HIV-1 infected patients virologically suppressed after a successful treatment with PI containing ART. Articles included in the analysis were published between 2001 and 2010, and could be classified as low risk of bias trials in most of the domains considered. Overall, there was no significant difference between the participants on triple nucleoside combination and controls, either PI-based or NNRTI based in terms of overall failures, death and AIDS related events, and rates of patients with viral load below the detectability cut-off. For the outcomes discontinuation for adverse events and virologic failures, the RRs were not significant , albeit  being not far from the alpha level of 0.05, thus suggesting a weak evidence of lower incidence of side effects  and an higher incidence of virologic failure in the 3NRTI group compared to controls . Change in lipids and in CD4 cells from baselines were reported in 7 studies, but inconsistency in reporting these data did not allow quantitative analysis. However, all agreed that simplification with ABC had a favourable and significant impact on lipid metabolism compared to control group. An increase in CD4 cells count from baseline was evident in all analysed studies, without significant differences between ABC and controls in individual studies. AUTHORS' CONCLUSIONS: The strategy of switching to triple nucleoside regimens shows weak evidence of lower incidence of side effects and a higher incidence of virologic failure in the 3NRTI group compared to controls. Simplification with 3NRTI holds the advantages of preserving other classes of antiretroviral drugs, to lower blood lipids, and to be cost effective and simple to administer.Thus, simplification with triple nucleoside regimens AZT + 3TC + ABC should be still considered for individuals who are unable to tolerate or have contraindications to NNRTI or PI based regimens. Additional data are needed on longer-term efficacy of triple NRTI regimens, particularly on the development of antiretroviral resistance. Though studies in the current review were conducted between 2001 and 2010, the large majority of patients from studies analysed received old PI regimens (e.g., indinavir, ritonavir, nelfinavir, saquinavir) not longer recommended by International Guidelines. Since current guidelines recommend new "lipid -friendly" PI, future studies should compare regimens containing these news PIs to triple NRTI regimens. More realistically, however, there are opportunities to examine these issues in existing cohorts.

Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data.

BACKGROUND: The use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease in some cohort studies. However, no excess risk of myocardial infarction (MI) with ABC therapy has been observed in individual randomized clinical trials (RCTs) and in the aggregated clinical trials database maintained by the manufacturer of ABC. OBJECTIVE: To combine all the evidence from RCTs by means of meta-analysis to estimate the effect of combined antiretroviral therapy (cART) containing ABC on MI and overall major cardiovascular events (CVEs). METHODS: Primary outcomes included MI, CVE, adverse events requiring discontinuation of treatment, and overall mortality. We used a conventional Mantel-Haenszel method, with risk ratio and 95% confidence intervals (CIs) or, in the presence of heterogeneity, a random-effect model. RESULTS: Data were from 28 primary RCTs (9233 participants) comparing ABC-containing cART (4376 participants) to other regimens not containing ABC (4857 controls). MI data were available from 18 trials (31 episodes in 7054 patients) and CVE data from 20 trials (79 episodes in 7899 patients). Compared to the controls, ABC use did not increase significantly the occurrence of MI (risk ratio 0.73, 95% CI 0.39-1.35; P = 0.31), CVE (risk ratio 0.95, 95% CI 0.62-1.44; P = 0.80), overall mortality (risk ratio 1.20, 95% CI 0.63-2.27; P = 0.58), and adverse events requiring discontinuation of treatment (risk ratio 0.82, 95% CI 0.67-1.00; P = 0.05). CONCLUSION: This meta-analysis of RCTs does not support the hypothesis that ABC-containing cART regimens carry a greater risk of MI or major cardiovascular events relative to comparator cART.

KSHV DNA viremia correlates with low CD4+ cell count in Italian males at the time of diagnosis of HIV infection.

To evaluate the relevance and the virological and immunological markers of Kaposi sarcoma herpesvirus 8 (KSHV) viremia in Italian male patients at the time of diagnosis of infection with HIV-1, 481 men infected with HIV were recruited consecutively. The presence of KSHV DNA was evaluated in peripheral blood mononuclear cells (PBMCs) and in plasma and correlated with demographic and viro-immunological parameters. Seventy-four patients had KSHV DNA detected in PBMCs. By univariate analysis, the presence of KSHV DNA was associated significantly with unprotected homosexual relationships (P=0.003) and it was significantly higher in patients with CD4+ cell <350 (P=0.025). By multivariate analysis, homosexual relationships were associated independently with KSHV DNA in PBMCs (OR: 3.25; 95% CI: 1.1-9.7; P=0.035). Among the 74 patients with KSHV DNA detected in PBMCs, plasma samples from 60 were analyzed and 33 were positive for KSHV DNA. The CD4+ cell counts and percentages were significantly lower in patients with KSHV DNA in both PBMCs and plasma as compared to patients with only KSHV DNA in PBMCs (P=0.006 and P=0.019, respectively). Among the patients with KSHV DNA detected in PBMCs, all 13 patients with CD4+ cells count <200 had detectable levels of KSHV in their plasma. By multivariate analysis adjusted for the epidemiologic and virological parameters, low CD4+ cell count was the only independent variable associated with the presence of KSHV DNA in plasma (OR, 0.001; 95% CI: <0.001-0.001; P=0.03). In HIV-positive antiretroviral therapy-naïve males, KSHV active replication as detected by KSHV DNA in plasma was associated significantly with low CD4+ cell count.

Granulocyte macrophage colony-stimulating factor as an adjuvant for hepatitis B vaccination: a meta-analysis.

The efficacy of granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance the immune response to hepatitis B virus vaccine has been object of several reports. We searched for randomized controlled clinical trials comparing GM-CSF given concomitantly to hepatitis B virus vaccine to vaccine given alone or with placebo. Data on rates of seroconversion (anti-HBs titers >10 IU/ml) from 13 studies (734 subjects) produced combined estimates that favored GM-CSF as compared to controls: rate ratio after a single immunization was 1.54 [95% confidence interval (CI), 1.04-2.27] and 1.20 (95% CI, 1.02-1.42) at the end of the vaccination cycle. Using a logistic approach a significant dose/response effect of GM-CSF was seen. Moreover, in renal failure patients who have responded to the vaccine, GM-CSF increased anti-HBs titers. Our findings suggest that GM-CSF induced a significant effect in terms of response rate and achievement of an earlier seroconversion to the vaccine in the overall populations examined, in renal failure patients and in healthy individuals.

Antifungal prophylaxis in liver transplant patients: a systematic review and meta-analysis.

We performed a meta-analysis to determine whether antifungal prophylaxis decreases infectious morbidity and mortality in liver transplant patients. We searched for randomized trials dealing with prophylaxis with systemic antifungal agents. We used a fixed effect model, with risk ratio (RR) and 95% confidence interval (CI); we assessed study quality for heterogeneity and publication bias. Six studies (5 double-blind), for a total of 698 patients, compared fluconazole, itraconazole, or liposomal amphotericin to placebo (5 studies) or oral nystatin. Prophylaxis reduced colonization (RR, 0.45; CI, 0.37-0.55), total proven fungal infections (RR, 0.31; CI, 0.21-0.46), which included both superficial (RR, 0.27; CI, 0.16-0.45) and invasive (RR, 0.33; CI, 0.18-0.59) infections, and mortality attributable to fungal infection (RR, 0.30; CI, 0.12-0.75). Prophylaxis did not affect overall mortality (RR, 1.06; CI, 0.69-1.64) or empiric treatment for suspected fungal infection (RR, 0.80; CI, 0.39-1.67). The beneficial effect of antifungal prophylaxis was predominantly associated with the reduction of Candida albicans infection and mortality attributable to C. albicans. Compared to controls, however, patients receiving prophylaxis experienced a higher proportion of episodes of non-albicans Candida, and in particular of C. glabrata. No beneficial effect on invasive Aspergillus infection was observed. In conclusion, our analysis shows a clear, though limited, beneficial effect of antifungal prophylaxis in liver transplant patients. Concerns about the selection of triazole-resistant Candida strains, however, are realistic, and the potential disadvantages of prophylaxis should be weighed against the established benefits.

Painful neuropathy vasculitis in 2 patients with long-standing human immunodeficiency virus-1 infection.

We describe 2 most unusual cases of distal symmetrical painful polyneuropathy in patients with long-standing HIV-1 infection well controlled by HAART. Sural nerve biopsies revealed vasculitis in both cases and steroid therapy led to resolution of symptoms not influenced by analgesics and anti-inflammatory drugs. These unusual cases outline the importance of nerve biopsies in order to reach a diagnosis.

Systematic review of the accuracy of the ParaSight-F test in the diagnosis of Plasmodium falciparum malaria.

BACKGROUND: The Parasight-F test is a device for the rapid diagnosis of Plasmodium falciparum malaria. In a number of field studies rather wide disparities in the performance of the test have been reported. To provide an evaluation of the quality of available reports and an overall summary of diagnostic accuracy of the Parasight-F test, we have performed a systematic review. MATERIAL/METHODS: Systematic review and meta-analysis of controlled studies evaluating the diagnostic accuracy of Parasight-F test in comparison with light microscopy. DATA SOURCES: 15,359 subjects (4,119 with falciparum malaria) studied with the Parasight-F test as reported in 32 studies from 29 publications. MAIN OUTCOME MEASURES: Summary receiving operator characteristic (SROC) curve as well as odds ratio calculated by the fixed effect model and the random effect model. Based on pooled data, the predictive values were calculated for a range of P. falciparum prevalence through a Bayesian approach. RESULTS: Overall, the Parasight-F test demonstrated 0.90 (95%, confidence intervals 0.88-0.93) sensitivity and 0.94 (0.92-0.96) specificity. Both sensitivity and specificity were significantly higher in the non-resident than in the resident population. The post-test probability indicates that in settings of low malaria prevalence, a negative test almost absolutely excludes infection, while in settings of high prevalence, the same result still gives a substantial chance of infection being present. CONCLUSIONS: The Parasight-F test is a simple and accurate test for the diagnosis of P. falciparum infection. The test could be of particular value in the diagnosis of malaria in travelers returning from endemic areas.

Reappraisal with meta-analysis of the addition of Gram-positive prophylaxis to fluoroquinolone in neutropenic patients.

PURPOSE: Past reports and meta-analyses indicate that fluoroquinolones are highly effective in preventing Gram-negative infections in neutropenic cancer patients, but offer inadequate coverage for Gram-positive infections. We evaluated by meta-analysis the efficacy of the addition of antimicrobial agents with enhanced Gram-positive activity to prophylaxis with quinolones. MATERIALS AND METHODS: Randomized trials comparing fluoroquinolones alone (ciprofloxacin, ofloxacin, pefloxacin, or norfloxacin) with fluoroquinolone in combination with Gram-positive prophylaxis (rifampin, vancomycin, amoxicillin, roxithromycin, or penicillin) were retrieved. We pooled relative risks (RRs) using a fixed-effects model. RESULTS: Nine trials (1,202 patients) published between 1993 and 2000 meet inclusion criteria. Compared with fluoroquinolone alone, Gram-positive prophylaxis reduced total bacteremic episodes (RR, 1.54; 95% CI, 1.26 to 1.88), streptococcal infections (RR, 2.20; 95% CI, 1.44 to 3.37), coagulase-negative staphylococcal infections (RR, 1.46; 95% CI, 1.04 to 2.04), and rate of febrile patients (RR 1.08; 95% CI, 1.00 to 1.16). Occurrence of clinically documented infections, unexplained fever, and infectious mortality was similar in the two groups. The addition of Gram-positive prophylaxis, however, significantly increased side effects (RR, 0.46; 95% CI, 0.28 to 0.76). Rifampin use resulted in a higher incidence of undesirable effects. CONCLUSION: Considering the lack of cut-clear benefit on some parameters of morbidity and mortality, routine use of Gram-positive prophylaxis is not advisable. This strategy, however, should be particularly valuable in subgroups of patients at high risk of streptococcal infection (eg, those with severe and prolonged neutropenia or mucositis, and those receiving cytarabine). Problems of tolerability and the potential for the emergence of resistant microorganisms should be considered when prescribing prophylaxis with enhanced Gram-positive activity to neutropenic patients.