The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers.

BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).RESULTSPCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONSThese results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.FUNDINGInstituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation.

Transmitted Drug Resistance and HIV Diversity Among Adolescents Newly Diagnosed With HIV in Spain.

BACKGROUND: Virologic characterization of newly HIV-diagnosed adolescents could help to improve their specific needs. The objective was to describe the transmitted drug resistance mutations (TDR) and its transmission by clusters in this population in Spain. METHODS: TDR to retrotranscriptase and protease inhibitors included in the WHO TDR list 2009 implemented in the Calibrated Population Resistance tool v8.0 (Stanford) were studied in HIV pol sequences from all HIV-diagnosed adolescents (12-19-year-old) enrolled during 2004-2019 period in the Spanish pediatric and adult (CoRISpe-CoRIS) cohorts. The found TDR were compared with the provided by the Stanford algorithm v9.0 2021. HIV-1 variants and transmission clusters were also studied. RESULTS: Among 410 HIV-1 adolescents diagnosed, 141 (34.4%) had available ART-naive sequences. They were mostly male (81.6%), Spanish (55.3%) and with behavioral risk (92.2%), mainly male-to-male sexual contact (63.1%). TDR prevalence was significantly higher by Stanford versus WHO list (18.4% vs. 7.1%; P = 0.004). The most prevalent TDR by the WHO list was K103N (3.6%) and by Stanford E138A (6.6%), both at retrotranscriptase. E138A, related to rilpivirine/etravirine resistance, was absent in the WHO list. One in 4 adolescents carried HIV-1 non-B variants. We described 5 transmission clusters, and 2 carried TDR mutations. CONCLUSIONS: Our data suggest a high TDR prevalence in adolescents with a new HIV diagnosis in Spain, similar to adults, 2 active TDR transmission clusters, and the need for the WHO TDR list update. These findings could have implications for the options of the recently available rilpivirine-related long-acting treatment and in first-line regimen election.

Rildo: Real-World Multicenter Study on the Effectiveness and Safety of Single-Tablet Regimen of Dolutegravir plus Rilpivirine in Treatment-Experienced People Living with HIV.

Two-drug regimens (2DRs) are emerging in clinical practice guidelines as treatment option for both naive and treatment-experienced people living with HIV (PLHIV). Objectives: To determine the real-life effectiveness of 2DR with 25 mg RPV plus 50 mg DTG in a single-tablet regimen (RPV/DTGSTR) and its impact on viral and immune status, lipid profile, and inflammatory markers. Methods: This observational study included 291 treatment-experienced PLHIV, starting 2DR with RPV/DTGSTR between 29 January 2019 and 2 February 2022, who were followed up for at least six months. Participants gave verbal informed consent for the switch in antiretroviral therapy (ART) to RPV/DTGSTR. Results: The mean age of the 291 participants was 51.3 years; 77.7% were male; and 42.9% were in the AIDS stage with a CD4 nadir of 283.5 ± 204.6 cells/uL. The median time since HIV diagnosis was 19.7 years (IQR: 10.6-27). Before 2DR, patients received a median of five ART lines (IQR: 3-7) for 22.2 years (IQR: 14-26), with 34.4% (n = 100) receiving a three-drug regimen (3DR), 31.3% (n = 91) receiving monotherapy, and 34.4% (n = 100) receiving 2DR. The median time on RPV/DTGSTR was 14 months (IQR: 9.5-21); 1.4% were lost to the follow-up. Effectiveness was 96.2% by intention-to-treat (ITT) analysis, 97.5% by modified ITT, and 99.3% by per-protocol analysis. Virological failure was observed in 0.69%, blips in 3.5%, and switch to another ART in 1.4%. The mean lipid profile improved, with reductions in TC/HDLc ratio (3.9 ± 0.9 vs. 3.6 ± 0.9; p = 0.0001), LDLc (118.3 ± 32.2 mg/dL vs. 106.2 ± 29.8 mg/dL, p = 0.0001), TG (130.9 ± 73.9 mg/dL vs. 115.9 ± 68.5 mg/dL, p = 0.0001), and CD4/CD8 ratio increase (0.99 ± 0.58 vs. 1.01 ± 0.54; p = 0.0001). The cost-effectiveness of 2DR with RPV/DTGSTR was similar to that of DTG/3TC and superior to those of BIC/TAF/FTC and DRV/c/TAF/FTC, with higher virological suppression and lower annual costs. Conclusions: The switch to RPV plus DTG in STR is a cost-effective, long-lasting, and robust strategy for PLHIV, with a very long experience of treatment, which improves the lipid profile without affecting inflammatory markers.

Hemophagocytic lymphohistiocytosis associated with Leishmania: A hidden passenger in endemic areas.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome characterized by excessive immune activation. We analyzed the presentation, diagnosis and prognosis of our cohort of HLH-Leishmania cases. METHODS: We studied HLH cases in patients over 14 years of age in the province of Granada (Spain), from January 2008 to November 2019. RESULTS: In this study, Leishmania was the predominant trigger of adult HLH in our region. There were no differences in the clinical-analytical presentation between HLH triggered by Leishmania and those initiated by a different cause. RT-PCR was the best tool to identify Leishmania as the trigger of HLH, given that the other microbiological tests showed low sensitivity to detect the parasite in our HLH-Leishmania cases. CONCLUSION: A comprehensive search for Leishmania is mandatory in HLH cases. Based on our findings, we propose that RT-PCR for Leishmania in bone marrow samples must be included in HLH differential diagnostic protocols.

Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.

BACKGROUND & AIMS: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. METHODS: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. RESULTS: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. LAY SUMMARY: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

Clinically atypical cutaneous mycobacteriosis: A therapeutic challenge.

Mycobacterium caprae, a member of the Mycobacterium tuberculosis complex, causes tuberculosis in humans and animals, but the incidence in humans is very low worldwide. Direct contact with animals and with unpasteurized dairy products is the most frequent source of contagion. Cutaneous tuberculosis supposes a diagnostic challenge due to its variety of clinical manifestations and the difficulty in demonstrating resistant acid-alcohol bacilli in histological samples. In cases of high suspicion, the initiation of antituberculosis treatment should be considered empirically. Combined therapeutic regimens are necessary to prevent long-term resistance and complications, although the duration of treatment has not been fully established.

[Evolution and treatment of storm cytoquine syndrome associated to SARS-CoV-2 infection among octogenarians]. / Tratamiento y evolución del síndrome de tormenta de citoquinas asociados a infección por SARS-CoV-2 en pacientes octogenarios.

INTRODUCTION: Cytokine storm syndrome (CTS) is a serious complication of patients with SARS-CoV-2 infection. Treatment and evolution in octogenarians are not well defined. Our objective is to describe its clinical characteristics, the treatments and its clinical evolution. PATIENTS AND METHOD: Retrospective observational study of consecutive patients admitted in the period between March 23 and April 12, 2020 with confirmed SARS-CoV-2 infection, with pneumonia by radiological study or chest tomography, whith STC criteria and who received treatment. We classified patients as those who received only glucocorticoid (GC) pulses, or GC and tocilizumab pulses. We determined serum levels of ferritin, CRP and D-dimers. The final variable was survival. RESULTS: 21 patients, (80-88 years). The mean ferritin was 1056 microg/L (317-3,553), CRP 115.8mg/dL (22-306) and D-dimers 2.9m/L (0.45-17.5). All patients received GC pulses and in 2 cases simultaneously tocilizumab. The mean follow-up time was 13.7 days (8-21). The overall mortality was 38.1% (8/21 patients). The 2 patients who received tocilizumab died. The deceased had significantly higher levels of ferritin (1,254 vs. 925microg/L; P=.045) and CRP (197.6 vs. 76mg / dL; P=.007). At the end of the follow-up, a decrease in the biochemical parameters was observed with ferritin of 727microg/L, CRP of 27mg/dl and D-dimers of 1.18mg/L. In 13/21 patients (61.9%), the CTS was controlled without the need to add other treatments. CONCLUSIONS: STC mortality from SARS-CoV-2 is high despite treatment. A greater inflammatory response was associated with a higher mortality. Although it seems that the early use of GC pulses could control it, and the use of other treatments such as tocilizumab shouldo be, with the study design and its limitations, this conclusion cannot be stablished.

Clinical predictors of candidemia in medical non-neutropenic, non-ICU patients. The CaMed score.

INTRODUCTION: Candida species are the leading cause of invasive fungal infections in hospitalised patients and are the fourth most common isolates recovered from patients with bloodstream infection. Few data exist on risk factors for candidemia in non-ICU patients. We performed a population-based case-control study to evaluate the main predictors for candidemia in non-ICU patients. METHODS AND FINDINGS: We included all non-neutropenic, non-critically ill and non-surgical adult patients with candidemia between January 2010 and June 2014. Patients with positive, non-candidal blood culture obtained at the same day (±2 days) were selected as controls. Cases and controls were matched according to hospital ward and clinical characteristics. Risk factors for candidemia were identified through a logistic regression. We included 56 candidemic and 512 bacteriemic non-candidemic patients. Most of candidemic patients (52) had received antibiotics prior to candidemia. Among them, the 30-day mortality rate was 34% (19/56). Multivariate analysis identified male sex, prior use of steroids, prior use of antibiotics, total parenteral nutrition and urinary catheterisation as independent predictors of candidemia. To develop the CaMed score, we rounded up weights of different risk factors as follows; total parenteral nutrition (+2), prior antibiotic therapy (+5), each of the other risk factors (+1). A score ≥ 7 identified patients at high risk of candidemia (P < 0.001; RR 29.805; CI 95% 10.652-83.397; sensitivity 79.2, specificity 82.6%, Youden index 0,62). CONCLUSIONS: Our set of easy independent predictors of candidemia in non-neutropenic, non-ICU, non-surgical patients provide a rationale for early initiation of antifungals and could reduce candidemia-related mortality.

Nebulized medication is not associated with nosocomial infections. A pilot study.

INTRODUCTION: Nebulized devices are commonly used in the treatment of respiratory infection, and other respiratory diseases. It has been reported nosocomial infections in cystic fibrosis patients as a result of the use of contaminated devices. However, little is known about nosocomial infections secondary to aerosolized therapy in COPD patients admitted for acute exacerbation. METHODS: Thirty consecutive patients (13 males) were included. All of them received aerosolized medication. Each patient used their own facemask and nebulizer cup, which were stored in the room after its use. Samples from nebulizer cups were obtained on days 0, 4 and 7. In addition, sputum samples were obtained on day 0 (prior to any nebulization) and on day 7, and cultivated in enriched media. RESULTS: Only nine nebulizer cups had positive microbiological cultures. Coagulase negative staphylococci (CoNS) were isolated in all cases. Sputum samples could be obtained in 27 patients. None grew CoNS after 7 days of aerosolized therapy. Gram-negative non-fermenting bacilli were isolated in three patients without concomitant grown in nebulizer cups. CONCLUSIONS: We did not find any nosocomial infection related to aerosolize medications in COPD patients admitted for acute exacerbation.

Predictors of early mortality in very elderly patients with bacteremia: a prospective multicenter cohort.

OBJECTIVES: The proportion of very elderly people in the population is increasing, and infectious diseases in this patient group may present with specific characteristics. The objective of this study was to investigate the outcome predictors of bacteremia among the very elderly. METHODS: This was a multicenter prospective cohort study of bloodstream infections (BSI) in patients ≥ 80 years old in 15 hospitals in Spain. The outcome variables were 14-day and 30-day mortality. Multivariate analysis was performed. RESULTS: One hundred and twenty episodes were included. Mortality was 22% (n = 26) on day 14 and 28% (n = 34) on day 30. In the univariate analysis, the variables associated with mortality were neutropenia, recent surgery, Pitt score ≥ 2, intensive care unit (ICU) admission, severe sepsis or shock, and abdominal, unknown, and respiratory tract sources. In the multivariate analysis, variables associated with mortality on day 14 were high-risk source (abdominal, unknown, and respiratory tract sources; odds ratio (OR) 7.9, 95% confidence interval (CI) 1.8-33.9), Pitt score ≥ 2 (OR 5.6, 95% CI 1.3-23.3), inadequate empirical treatment (OR 11.24, 95% CI 1.6-80.2), and severe sepsis or shock at presentation (OR 5.3, 95% CI 1.4-20.7); the interaction between empiric treatment and high-risk source was significant. On day 30, mortality was independently related to a high-risk source (OR 2.92, 95% CI 1.1-7.5) and presentation with severe sepsis or shock (OR 3.81, 95% CI 1.2-12.4). CONCLUSIONS: Presentation with severe sepsis or shock and a high-risk source of BSI were independent predictors of 14-day and 30-day mortality. Inadequate empirical treatment was also a predictor of early mortality in patients with a high-risk source.

Protease inhibitor monotherapy is not associated with increased viral replication in lymph nodes.

There are concerns about residual viremia in sanctuary sites among patients on protease inhibitor monotherapy, so we aimed to study viro-immunological parameters in tonsil's lymphoid tissue of patients on highly active antiretroviral therapy (HAART) and on protease inhibitor monotherapy. Despite fully suppressed serum HIV viral load, we found viral replication in both groups; in addition, more patients had detectable proviral DNA among those on HAART, compared to those on protease inhibitor monotherapy (P = 0.08), supporting the absence of a deleterious effect of protease inhibitor monotherapy.

Quantification of viral loads lower than 50 copies per milliliter by use of the Cobas AmpliPrep/Cobas TaqMan HIV-1 test, version 2.0, can predict the likelihood of subsequent virological rebound to >50 copies per milliliter.

After 1 year of follow-up, patients on HAART with a baseline viral load (VL) of <20 copies/ml showed significantly lower odds of virological rebound to two consecutive VLs of >50 copies/ml than those with baseline VLs of 20 to 39 and 40 to 49 (P < 0.001). The time to virological rebound was also significantly shorter (P < 0.001) for the groups with baseline VLs of 20 to 39 and 40 to 49.