Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial.

BACKGROUND: Lenacapavir, a first-in-class HIV-1 capsid inhibitor, is in development as a long-acting agent for treating and preventing HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen in adults living with multidrug-resistant HIV-1 up to 52 weeks. METHODS: This ongoing, international, phase 2/3 trial at 42 sites included adults living with multidrug-resistant HIV-1. In cohort 1, 36 participants were randomly assigned (2:1) to add oral lenacapavir (600 mg, days 1 and 2; 300 mg, day 8) or placebo to an existing failing regimen. At day 15, those on oral lenacapavir received subcutaneous lenacapavir 927 mg every 26 weeks; those on placebo started lenacapavir (2-week oral lead-in then subcutaneous). Cohort 1 started an optimised background regimen on day 15. In cohort 2 (non-randomised), 36 participants started an optimised background regimen concurrent with lenacapavir (oral to subcutaneous). Here we report the secondary endpoints of plasma HIV-1 RNA of less than 50 copies per mL or less than 200 copies per mL at week 52 (US Food and Drug Administration snapshot algorithm) in cohort 1 along with results for cohorts 1 and 2 combined. This trial is registered with ClinicalTrials.gov, NCT04150068, and clinicaltrialregister.eu, EudraCT 2019-003814-16 and is ongoing. FINDINGS: Of 72 participants, 46 (64%) had CD4 counts of less than 200 cells per µL and 38 (53%) had no more than one fully active antiretroviral drug at baseline. In cohort 1, 30 of 36 participants (83%, 95% CI 67-94) had less than 50 HIV-1 RNA copies per mL and 31 of 36 participants (86%, 71-95) had less than 200 HIV RNA copies per mL, at week 52. In all, nine participants (four in cohort 1, five in cohort 2) had emergent lenacapavir resistance; four resuppressed (HIV-1 RNA <50 copies per mL) while maintaining lenacapavir use. One participant discontinued study drug owing to injection site reaction. INTERPRETATION: In participants with multidrug-resistant HIV-1, subcutaneous lenacapavir in combination with an optimised background regimen resulted in a high rate of virological suppression up to 52 weeks. FUNDING: Gilead Sciences.

A case of Lactobacillus jensenii associated native valve endocarditis.

Lactobacillus jensenii is rarely reported as a cause of endocarditis in immunocompetent patients. We describe a case of Lactobacillus jensenii associated native valve endocarditis that was identified using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) technology. While most Lactobacillus species are generally resistant to vancomycin, Lactobacillus jensenii is frequently susceptible, but treatment requires accurate susceptibility results followed by timely medical and surgical intervention. Probiotic use in patients can be a risk factor for infection with Lactobacillus species.

Omadacycline for the treatment of Mycobacterium abscessus infections: Case series and review of the literature.

Treatment of Mycobacterium abscessus infections are problematic due to inherent multidrug resistance and lack of response to antibacterials commonly used as therapy for other mycobacterial infections. We report the clinical success of five patients who received definitive-treatment with an omadacycline-containing combination regimen for M. abscessus infection.

Early Introduction and Community Transmission of SARS-CoV-2 Omicron Variant, New York, New York, USA.

The Omicron variant of SARS-CoV-2 has become dominant in most countries and has raised significant global health concerns. As a global commerce center, New York, New York, USA, constantly faces the risk for multiple variant introductions of SARS-CoV-2. To elucidate the introduction and transmission of the Omicron variant in the city of New York, we created a comprehensive genomic and epidemiologic analysis of 392 Omicron virus specimens collected during November 25-December 11, 2021. We found evidence of 4 independent introductions of Omicron subclades, including the Omicron subclade BA.1.1 with defining substitution of R346K in the spike protein. The continuous genetic divergence within each Omicron subclade revealed their local community transmission and co-circulation in New York, including both household and workplace transmissions supported by epidemiologic evidence. Our study highlights the urgent need for enhanced genomic surveillance and effective response planning for better prevention and management of emerging SARS-CoV-2 variants.

SARS-CoV-2 Continuous Genetic Divergence and Changes in Multiplex RT-PCR Detection Pattern on Positive Retesting Median 150 Days after Initial Infection.

Being in the epicenter of the COVID-19 pandemic, our lab tested 193,054 specimens for SARS-CoV-2 RNA by diagnostic multiplex reverse transcription polymerase chain reaction (mRT-PCR) starting in March 2020, of which 17,196 specimens resulted positive. To investigate the dynamics of virus molecular evolution and epidemiology, whole genome amplification (WGA) and Next Generation Sequencing (NGS) were performed on 9516 isolates. 7586 isolates with a high quality were further analyzed for the mutation frequency and spectrum. Lastly, we evaluated the utility of the mRT-PCR detection pattern among 26 reinfected patients with repeat positive testing three months after testing negative from the initial infection. Our results show a continuation of the genetic divergence in viral genomes. Furthermore, our results indicate that independent mutations in the primer and probe regions of the nucleocapsid gene amplicon and envelope gene amplicon accumulate over time. Some of these mutations correlate with the changes of detection pattern of viral targets of mRT-PCR. Our data highlight the significance of a continuous genetic divergence on a gene amplification-based assay, the value of the mRT-PCR detection pattern for complementing the clinical diagnosis of reinfection, and the potential for WGA and NGS to identify mutation hotspots throughout the entire viral genome to optimize the design of the PCR-based gene amplification assay.

Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study. METHODS: In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26. RESULTS: A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions). CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).

Implementation of a Collaborated Antimicrobial Stewardship Program and Outpatient Parenteral Antimicrobial Therapy (OPAT) Unit-driven Monoclonal Antibody Therapy Program for COVID-19 at an NYC Hospital.

OBJECTIVES: This study aimed to assess the processes and clinical outcomes of a joint collaboration between Antimicrobial Stewardship Program (ASP) and the outpatient parenteral antimicrobial therapy (OPAT) unit for delivery of monoclonal antibody therapy for mild-to-moderate COVID-19. METHODS: We carried out a retrospective, interim analysis of our COVID-19 monoclonal antibody therapy program. Outcomes included clinical response, incidence of hospitalization, and adverse events. RESULTS: A total of 175 patients (casirivimab-imdevimab, n = 130; bamlanivimab, n = 45) were treated between December 2020 and March 1, 2021. The median time from symptom onset was 6 (IQR 4, 8) days at time of treatment. Of 135 patients available for follow-up, 71.9% and 85.9% of patients reported symptom improvement within 3 and 7 days of treatment, respectively. A total of 9 (6.7%) patients required COVID-19-related hospitalization for progression of symptoms, all within 14 days of treatment. A total of 7 (4%) patients experienced an infusion-related reaction. CONCLUSIONS: ASP-OPAT collaboration is a novel approach to implement an efficient and safe monoclonal antibody therapy program for the treatment of mild-to-moderate COVID-19.

Combination antibiotic therapy for treatment of a patient with infected prosthesis and peri-prosthetic abscess due to Klebsiella pneumoniae harboring New Delhi Metallo (NDM) beta-lactamase.

Treatment options for patients infected with multi-drug resistant gram-negative bacteria harboring metallo-beta-lactamases (MBLs) requires precision therapy. We present the case of a 20 year-old male with a right distal femoral peri-prosthetic abscess with presumed infected hardware and osteomyelitis in whom four multi-drug resistant gram negative bacteria were isolated. The rapid identification of an MBL producing organism, novel combination of therapy, and prompt infection prevention enforcement and education led to appropriate treatment of our patient as well as prevention of spread of organisms during and after hospitalization. This case illustrated successful management of multiple challenges faced by patients infected and/or harboring extensively resistant bacteria.

Fatal case of disseminated cryptococcal infection and meningoencephalitis in the setting of prolonged glucocorticoid use in a Covid-19 positive patient.

Based on the RECOVERY trial, glucocorticoids have become the mainstay of treatment for COVID-19, thus increasing the risk of opportunistic infections. We report a case of disseminated Cryptococcus neoformans with documented meningoencephalitis in a patient with severe COVID-19 in the setting of prolonged glucocorticoid administration with poor outcome likely due to adrenal involvement.

Co-Infection with 4 Species of Mycobacteria Identified by Using Next-Generation Sequencing.

We identified co-infection with 4 species of mycobacteria in a woman in New York, New York, USA, by using next-generation sequencing. This procedure is useful for identifying co-infections with multiple mycobacteria, tracing the geographic origin of strains, investigating transmission dynamics in susceptible populations, and gaining insight into prevention and control.

Streptococcus pseudoporcinus: Case Reports and Review of the Literature.

Streptococcus pseudoporcinus is a beta-hemolytic Gram-positive, catalase-negative, nonmotile coccus arranged in short chains, usually found in the female genitourinary tract and differentiated from Streptococcus porcinus in 2006. Only two human infections associated with this organism have been reported to date: one in a patient with a first digit wound infection and another with lower extremity cellulitis. We describe two novel cases of Streptococcus pseudoporcinus causing endocarditis in one and pneumonia with empyema in another, illustrating the potential of these bacteria to cause severe invasive and life-threatening disease.

Superior Efficacy and Improved Renal and Bone Safety After Switching from a Tenofovir Disoproxil Fumarate- to a Tenofovir Alafenamide-Based Regimen Through 96 Weeks of Treatment.

We previously demonstrated superior efficacy and safety advantages in HIV-infected, virologically suppressed adults switched to a regimen containing tenofovir alafenamide (TAF) as compared with those remaining on a tenofovir disoproxil fumarate (TDF) regimen through week 48. We now report long-term data through week 96. In this randomized, active-controlled, multicenter, open-label, noninferiority trial (ClinicalTrials.gov No. NCT01815736), we randomized virologically suppressed (HIV-1 RNA <50 copies/ml) adults (2:1) to receive a once-daily, single-tablet regimen containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and TAF group or to continue one of four TDF-containing regimens (TDF group) for 96 weeks. We evaluated efficacy (HIV-1 RNA <50 copies/ml using the FDA snapshot algorithm) and prespecified bone and renal endpoints at week 96. We randomized and treated 1,436 participants in this study (TAF n = 959, TDF n = 477). At week 96, TAF was superior to TDF in virologic efficacy, with 93% on TAF and 89% on TDF having HIV-1 RNA <50 copies/ml (difference 3.7%, 95% confidence interval: 0.4%-7.0%). Improvements in hip and spine bone mineral density for those assigned to TAF versus TDF continued through week 96 (p < .001). Significant improvements in urine protein or albumin to creatinine ratios were also seen among those in the TAF group versus TDF through week 96 (p < .001). There were no cases of investigator-reported proximal renal tubulopathy in the TAF group as compared with one case in the TDF group. Switching to EVG/COBI/FTC/TAF (E/C/F/TAF) was associated with statistically significant efficacy and safety advantages over remaining on a standard-of-care TDF-based regimen.

Tuberculosis in Enclosed Populations.

Transmission of tuberculosis (TB) is most effective in close contact indoor environments in various congregate settings including health care facilities, homeless shelters, correctional facilities, long-term care facilities, as well as community settings such as homes, schools, workplaces, and various modes of transportation. Outbreaks are fueled by numerous factors including the HIV epidemic, ease of global travel, unstable socio-economic and/or political situations, and lapses in response to potentially infectious patients. Organized approaches to TB control include an appropriate index of suspicion, identification and isolation of contagious patients in appropriate facilities, use of environmental controls, and personal protective equipment in accordance to national and international published guidelines. These all require tailoring to the various settings where TB is encountered using a determination of risk. Concerted efforts at the local, regional, national, and international levels at identifying patients with active disease, enforcing completion of treatment, and testing and fully treating patients with latent TB infection are paramount in reducing TB burden and continued transmission.

Asymptomatic rectal colonization with carbapenem-resistant Enterobacteriaceae and Clostridium difficile among residents of a long-term care facility in New York City.

BACKGROUND: Residents of long-term care facilities (LTCFs) are at increased risk for colonization and development of infections with multidrug-resistant organisms. This study was undertaken to determine prevalence of asymptomatic rectal colonization with Clostridium difficile (and proportion of 027/NAP1/BI ribotype) or carbapenem-resistant Enterobacteriaceae (CRE) in an LTCF population. METHODS: Active surveillance was performed for C difficile and CRE rectal colonization of 301 residents in a 320-bed (80-bed ventilator unit), hospital-affiliated LTCF with retrospective chart review for patient demographics and potential risk factors. RESULTS: Over 40% of patients had airway ventilation and received enteral feeding. One-third of these patients had prior C difficile-associated infection (CDI). Asymptomatic rectal colonization with C difficile occurred in 58 patients (19.3%, one-half with NAP1+), CRE occurred in 57 patients (18.9%), and both occurred in 17 patients (5.7%). Recent CDI was significantly associated with increased risk of C difficile ± CRE colonization. Multivariate logistic regression analysis revealed presence of tracheostomy collar to be significant for C difficile colonization, mechanical ventilation to be significant for CRE colonization, and prior CDI to be significant for both C difficile and CRE colonization. CONCLUSIONS: The strong association of C difficile or CRE colonization with disruption of normal flora by mechanical ventilation, enteral feeds, and prior CDI carries important implications for infection control intervention in this population.

Rilpivirine vs. efavirenz-based single-tablet regimens in treatment-naive adults: week 96 efficacy and safety from a randomized phase 3b study.

OBJECTIVES: To compare efficacy, safety, tolerability, and patient-reported outcomes between two single-tablet regimens, rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults. DESIGN: This was a phase 3b, 96-week, randomized, open-label, international, noninferiority trial. METHODS: A total of 799 participants were randomized (1 : 1) to receive RPV/FTC/TDF or EFV/FTC/TDF. The primary efficacy endpoint evaluated proportions of participants with HIV-1 RNA less than 50 copies/ml using the Snapshot algorithm. Additional assessments included CD4 cell counts, genotypic/phenotypic resistance, adverse events, patient-reported outcomes, and quality of life questionnaires. RESULTS: At week 96, trial completion rates were 80.2% (316/394; RPV/FTC/TDF) and 74.0% (290/392; EFV/FTC/TDF). Overall, RPV/FTC/TDF was noninferior to EFV/FTC/TDF [HIV-1 RNA <50 copies/ml: 77.9 vs. 72.4%, respectively; difference -5.5; 95%CI (-0.6, 11.5); P = 0.076]. RPV/FTC/TDF was significantly more efficacious compared with EFV/FTC/TDF in participants with baseline HIV-1 RNA equal to or less than 100 000 copies/ml (78.8 vs. 71.2%; P = 0.046) and in those with CD4 cell count greater than 200 cells/µl (80.6 vs. 73.0%; P = 0.018). There was no significant between-group difference in the CD4 cell count increase (278 ±â€Š189 vs. 259 ±â€Š191 cells/µl; P = 0.17). Few participants developed resistance after week 48 (1.0% RPV/FTC/TDF; 0.3% EFV/FTC/TDF). Compared with EFV/FTC/TDF, RPV/FTC/TDF was associated with fewer adverse event-related discontinuations (3.0 vs. 11.0%; P<0.001), significantly fewer adverse events due to central nervous system issues and rash, greater improvements in patient-reported symptoms, and significant improvements in the SF-12v2 quality of life questionnaire mental health composite score (P = 0.014). CONCLUSION: In treatment-naive, HIV-1-infected participants, 96-week RPV/FTC/TDF treatment demonstrated noninferior efficacy and better tolerability than EFV/FTC/TDF.

Evaluation of Remel Spectra CRE Agar for Detection of Carbapenem-Resistant Bacteria from Rectal Swabs Obtained from Residents of a Long-Term-Care Facility.

We compared the Remel Spectra CRE agar plate to CDC standard methodology for the isolation of carbapenem-resistant Enterobacteriaceae (CRE) from 300 rectal swab specimens obtained from patients residing in a long-term-care facility (LTCF). Multiplex PCR experiments were performed on isolates to identify specific Klebsiella pneumoniae carbapenemases (KPC) and additional ß-lactamases. Of the 300 patients, 72 (24%) harbored CRE and were PCR positive for KPC enzymes. The Remel Spectra CRE plates detected KPC-type CRE in isolates from 70 of 72 patients (97.2%), while the CDC method detected CRE in 56 of 72 (77.8%). CRE identification results were available in 18 h compared to 36 h for the CDC method. Remel Spectra CRE agar plates can provide useful means for a fast and reliable method for detecting KPC-type CRE and for accelerated institution of appropriate infection control precautions.

High prevalence of low skeletal muscle mass associated with male gender in midlife and older HIV-infected persons despite CD4 cell reconstitution and viral suppression.

Therapeutic goals for HIV-infected patients receiving antiretroviral therapy include minimizing risk of future physical disability. Presarcopenia and sarcopenia precede age-associated physical disability. We investigated their prevalence and the predictive value of patient mid-upper arm circumference (MUAC) for them. Eighty community-dwelling patients ≥45 years old demonstrating durable viral suppression were evaluated. Sarcopenia was defined as low skeletal muscle index (SMI, skeletal muscle kg/height m(2)) and either low strength or poor performance by handgrip dynamometry and gait speed, respectively. Presarcopenia was defined as low SMI only. MUAC was interpreted according to National Health Statistics percentile. Prevalence of sarcopenia and presarcopenia was 5.0% and 20.0%, respectively. Male gender (odds ratio [OR] 10.72; P < .026), recreational psychoactive substance use (OR 5.13; P < .037), and intravenous drug use transmission category (OR 6.94; P <.0327) were associated with presarcopenia. Higher body mass index (OR 0.80; P < .0007), MUAC (OR 0.83; P < .024), and large skeletal frame (OR 0.09; P < .003) were negatively associated with presarcopenia. Finding that a participant did not have a MUAC <25th percentile on physical examination had a 90.4% negative predictive value for presarcopenia. Although sarcopenia was uncommon, presarcopenia was highly prevalent in midlife and older HIV-infected males. Determination of MUAC percentile may identify those least likely to demonstrate skeletal muscle deficit and improve patient selection for mass and function testing.

Unrelated strain methicillin-resistant Staphylococcus aureus colonization of health care workers in a neonatal intensive care unit: findings of an outbreak investigation.

Three neonates and 5 health care workers were identified as colonized with methicillin-resistant Staphylococcus aureus (MRSA) out of 222 individuals screened during an outbreak investigation in an 18-bed neonatal intensive care unit. Two of 3 MRSA neonatal isolates demonstrated identical pulsed-field gel electrophoresis clonal patterns but no clonal association was found among isolates from the 5 employees or between employees and neonates. Increased MRSA-unrelated strain colonization among health care workers supports increased MRSA community prevalence and probable decreased utility of mass screening.

Identification of extended-spectrum-ß-lactamase-positive Klebsiella pneumoniae urinary tract isolates harboring KPC and CTX-M ß-lactamases in nonhospitalized patients.

Forty-seven extended-spectrum-ß-lactamase-positive Klebsiella pneumoniae urinary tract isolates from nonhospitalized patients were identified, and 79% harbored KPC and/or CTX-M ß-lactamases. Approximately 90% of the isolates were resistant to trimethoprim-sulfamethoxazole and levofloxacin, and 40% were resistant to a carbapenem, while 92% were susceptible to polymyxin B, 87% were susceptible to tigecycline, and 79% were susceptible to fosfomycin. Increased use of broader-spectrum antibiotics may help to prevent their dissemination and reduce the risk of progression to invasive disease.