Indira Brar

Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: A randomized phase 2 study

Objectives:To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of a single-tablet regimen (STR) for the initial treatment of HIV-1 infection. Design:Phase 2, randomized, double-blind, double-dummy, multicenter, active-controlled study. Methods:Antiretroviral naive adults with HIV-1 RNA ≥5000 copies per milliliter and a CD4 count ≥50 cells per microliter were randomized 2:1 to receive an STR of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo for 48 weeks. Results:Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates of virologic suppression (<50 HIV copies per milliliter) at week 24 (86.6%; 89.7%) and at week 48 (88.4%; 87.9%), and had similar improvements in CD4 at week 48 (177; 204), respectively. Both treatments were well tolerated, and most adverse events were self-limiting and of mild to moderate severity. Compared with patients on E/C/F/TDF, patients on E/C/F/TAF had smaller reductions in estimated creatinine clearance (−5.5 vs. −10.1 mL/min, P = 0.041), significantly less renal tubular proteinuria, and smaller changes in bone mineral density for hip (−0.62% vs. −2.39%, P < 0.001) and spine (−1.00% vs. −3.37%, P < 0.001). Patients on E/C/F/TAF had higher increases in total cholesterol, low-density lipoprotein, and high-density lipoprotein, but the total cholesterol/high-density lipoprotein ratio was unchanged for both. Conclusions:Treatment-naive patients given the STR that contained either TAF or TDF achieved a high rate of virologic success. Compared with those receiving TDF, patients on E/C/F/TAF experienced significantly smaller changes in estimated creatinine clearance, renal tubular proteinuria, and bone mineral density.

Spectrum of Bacille Calmette-Guérin (BCG) Infection after Intravesical BCG Immunotherapy

Intravesical instillation of bacille Calmette-Guérin (BCG) effectively treats transitional cell carcinoma of the bladder. Occasionally, BCG infection complicates such treatment. In some patients, infection appears early (within 3 months after instillation) and is characterized by generalized symptoms, with pneumonitis and hepatitis. Late-presentation disease occurs >1 year after the first BCG treatment and usually involves focal infection of the genitourinary tract (the site at which bacteria were introduced) and/or other sites that are typical for reactivation of mycobacterial disease, such as the vertebral spine or the retroperitoneal tissues. Noncaseating granulomas are found in the majority of cases, whether early or late. Most patients respond to treatment with antituberculous drugs; in early-presentation disease, when features of hypersensitivity predominate, glucocorticosteroids are sometimes added. Late localized infection often requires surgical resection.

Progressive Multifocal Leukoencephalopathy and Idiopathic CD4+Lymphocytopenia: A Case Report and Review of Reported Cases

Progressive multifocal leukoencephalopathy (PML) is a well recognized demyelinating neurological disorder caused by JC virus. Idiopathic CD4(+) lymphocytopenia (ICL) is a syndrome first described by the Centers for Disease Control and Prevention as a CD4(+) count <300 cells/mm(3) or a CD4(+) count that is <20% of the total T cell count on 2 occasions, with no evidence of human immunodeficiency virus (HIV) infection on testing, and absence of any defined immunodeficiency or therapy that depresses the levels of CD4(+) T cells. To the best of our knowledge, this is the third reported case of PML and ICL, and also the first reported case of the use of cidofovir to treat PML in a patient not infected with human immunodeficiency virus.

Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial

BACKGROUND Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug-drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine. METHODS We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per μL, 50-199 cells per μL, or ≥200 cells per μL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. All participants who received one dose of study drug were included in primary efficacy and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02607930. FINDINGS Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92·4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93·0% of patients (n=293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference -0·6%, 95·002% CI -4·8 to 3·6; p=0·78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p<0·0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p<0·0001). INTERPRETATION At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non-inferior to coformulated dolutegravir, abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting. FUNDING Gilead Sciences.

Latent Infection as a Source of Disseminated Disease Caused by Organisms of the Mycobacterium avium Complex in Simian Immunodeficiency Virus-Infected Rhesus Macaques

Whether infection with Mycobacterium avium complex (MAC) among patients with acquired immune deficiency syndrome results from recent exposure to virulent strains or reactivation of latent infection acquired years earlier is unknown. To address this question, tissue samples from 47 simian immunodeficiency virus (SIV)-infected and 63 SIV-uninfected rhesus macaques were cultured. MAC was cultured from 14 SIV-uninfected macaques (22.2%) and 32 SIV-infected macaques (68.1%); median bacterial burdens were 33.3 and 998.7 cfu/g, respectively. Genetically distinct strains of MAC were identified for 13 SIV-uninfected macaques (20.6%) and 15 SIV-infected macaques (31.9%). A genetically identical MAC strain (K128A) was identified for 25 SIV-infected macaques (53.2%) and 1 SIV-uninfected macaque (1.6%). Multivariate analysis identified infection with SIV/Delta(B670), diagnosis of an SIV-related tumor or opportunistic infection, and birth on site as risks for MAC infection. SIV-uninfected and SIV-infected macaques yielding unique strains of MAC were considered to have latent and reactivation infection, respectively, whereas animals infected with strain K128A were considered to have recent infection, demonstrating that both mechanisms occur among rhesus macaques.

Health disparities in hepatitis C screening and linkage to care at an integrated health system in southeast Michigan

With recommended screening for hepatitis C among the 1945–1965 birth cohort and advent of novel highly effective therapies, little is known about health disparities in the Hepatitis C care cascade. Our objective was to evaluate hepatitis C screening rates and linkage to care, among patients who test positive, at our large integrated health system. We used electronic medical records to retrospectively identify patients, in the birth cohort, who were seen in 21 Internal Medicine clinics from July 2014 to June 2015. Patients previously screened for hepatitis C and those with established disease were excluded. We studied patients’ sociodemographic and medical conditions along with provider-specific factors associated with likelihood of screening. Patients who tested positive for HCV antibody were reviewed to assess appropriate linkage to care and treatment. Of 40,561 patients who met inclusion criteria, 21.3% (8657) were screened, 1.3% (109) tested positive, and 30% (30/100) completed treatment. Multivariate logistic regression showed that African American race, male gender, electronic health engagement, residency teaching clinic visit, and having more than one clinic visit were associated with higher odds of screening. Patients had a significant decrease in the likelihood of screening with sequential interval increase in their Charlson comorbidity index. When evaluating hepatitis C treatment in patients who screened positive, electronic health engagement was associated with higher odds of treatment whereas Medicaid insurance was associated with significantly lower odds. This study shows that hepatitis C screening rates and linkage to care continue to be suboptimal with a significant impact of multiple sociodemographic and insurance factors. Electronic health engagement emerges as a tool in linking patients to the hepatitis C care cascade.

Late presentation and transmitted drug resistance mutations in new HIV-1 diagnoses in Detroit

OBJECTIVE To characterize the epidemiology and transmitted drug resistance mutation (TDRM) patterns among individuals with newly diagnosed HIV-1 infection seen at Henry Ford Hospital in Detroit from 2006 to 2008. METHODS This was a retrospective analysis of medical records from individuals aged ≥ 18 years with a new diagnosis of HIV-1 infection. Individuals who underwent genotypic resistance testing were included in the study. RESULTS One hundred thirty-three individuals were included; 99 (74%) were males, 104 (78%) were African-Americans, and 61 (46%) had a CD4+ count of ≤ 200 cells/μl. The prevalence of TDRM was 17% (23/133). Non-nucleoside reverse transcriptase mutations occurred in 11 (8%), nucleoside reverse transcriptase mutations in 13 (10%), and protease inhibitor mutations in 10 (8%). CD4+ count >350 cells/μl and HIV viral load on presentation were associated with TDRM in the multivariate analysis (p=0.004 and p<0.001 respectively). CONCLUSIONS Late diagnosis of HIV-1 and transmitted antiretroviral resistance are relatively common in Detroit. While most newly diagnosed persons were candidates for antiretroviral therapy on presentation, the high prevalence of TDRM has significant implications in the selection of first-line highly active antiretroviral therapy (HAART).

Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial

BACKGROUND Bictegravir, co-formulated with emtricitabine and tenofovir alafenamide, has shown good efficacy and tolerability, and similar bone, renal, and lipid profiles to dolutegravir, abacavir, and lamivudine, in treatment-naive adults with HIV-1 infection, without development of treatment-emergent resistance. Here, we report 48-week results of a phase 3 study investigating switching to bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine in virologically suppressed adults with HIV-1 infection. METHODS In this multicentre, randomised, double-blind, active-controlled, non-inferiority, phase 3 trial, HIV-1-infected adults were enrolled at 96 outpatient centres in nine countries. Eligible participants were aged 18 years or older and on a regimen of 50 mg dolutegravir, 600 mg abacavir, and 300 mg lamivudine (fixed-dose combination or multi-tablet regimen); had an estimated glomerular filtration rate of 50 mL/min or higher; and had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 3 months or more before screening. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg; herein known as the bictegravir group), or to remain on dolutegravir, abacavir, and lamivudine (herein known as the dolutegravir group), once daily for 48 weeks. The investigators, participants, study staff, and individuals assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (according to the US Food and Drug Administration snapshot algorithm); the prespecified non-inferiority margin was 4%. The primary efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting participants and is in the open-label extension phase, wherein participants are given the option to receive bictegravir, emtricitabine, and tenofovir alafenamide for an additional 96 weeks. This trial is registered with ClinicalTrials.gov, number NCT02603120. FINDINGS Between Nov 11, 2015, and July 6, 2016, 567 participants were randomly assigned and 563 were treated (282 received bictegravir, emtricitabine, and tenofovir alafenamide, and 281 received dolutegravir, abacavir, and lamivudine). Switching to the bictegravir regimen was non-inferior to remaining on dolutegravir, abacavir, and lamivudine for the primary outcome: three (1%) of 282 in the bictegravir group had HIV-1 RNA of 50 copies per mL or higher at week 48 versus one (<1%) of 281 participants in the dolutegravir group (difference 0·7%, 95·002% CI -1·0 to 2·8; p=0·62). Treatment-related adverse events were recorded in 23 (8%) participants in the bictegravir group and 44 (16%) in the dolutegravir group. Treatment was discontinued because of adverse events in six (2%) participants in the bictegravir group and in two (1%) participants in the dolutegravir group. INTERPRETATION The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection. FUNDING Gilead Sciences.

CURB-65 and SMRT-CO in the prediction of early transfers to the intensive care unit among patients with community-acquired pneumonia initially admitted to a general ward†

BACKGROUND No study has assessed the ability of pneumonia severity scores to identify the risk for early intensive care unit (ICU) transfer in patients with community-acquired pneumonia (CAP) admitted to general wards (GW). We aimed to compare the ability of CURB-65 (confusion, urea level, respiratory rate, blood pressure, and age ≥65 years) and SMRT-CO (systolic blood pressure, multilobar chest radiography involvement, respiratory rate, tachycardia, confusion, and oxygenation) scores to predict early ICU transfers in these patients. DESIGN Retrospective, case-control study. Cases were defined as patients admitted to GW with CAP that required ICU transfer within 48 hours. Controls were defined as patients admitted to GW with CAP that did not require ICU transfer. CURB-65 and SMRT-CO scores were calculated on presentation to emergency department (ED), and upon admission to GW. Composite scores were calculated combining data from ED and GW. Sensitivities, specificities, likelihood ratios, and areas-under-the-curve (AUC) were calculated for each score. RESULTS From 2003 to 2009, 115 cases and 345 controls were identified. Both groups had similar baseline characteristics. Composite scores combining data from ED and GW had better sensitivity and AUC than scores calculated only with ED or GW data (P < 0.001). A composite SMRT-CO score ≥2 had 76.5% (95% CI, 67.7 to 83.9) sensitivity, 67.5% (95% CI, 62.3 to 72.4) specificity, and 0.81 (95% CI, 0.77 to 0.85) AUC. A composite CURB-65 score ≥3 had 36.5% (95% CI, 27.7 to 46.0) sensitivity, 86.3% (95% CI, 82.3 to 89.8) specificity, and 0.66 (95% CI, 0.60 to 0.72) AUC to predict early ICU transfers. Composite SMRT-CO had higher sensitivity and AUC (P < 0.001) than composite CURB-65. CONCLUSIONS Composite SMRT-CO had a better combination of sensitivity and specificity than CURB-65 for predicting early ICU transfers. Prospective studies to confirm our findings are needed.

Antimicrobial stewardship: Strategies for a global response

The increasing antimicrobial resistance worldwide, combined with dwindling antimicrobial armamentarium, has resulted in a critical threat to the public health and safety of patients. To combat this hazard, antimicrobial stewardship programs (ASPs) have emerged. Antimicrobial stewardship programs prevent or slow the emergence of antimicrobial resistance by coordinated interventions designed to optimize antimicrobial use to achieve the best clinical outcomes and limiting selective pressures that drive the emergence of resistance. This also reduces excessive costs attributable to suboptimal antimicrobial use. Even though an ideal effective ASP should incorporate more than one element simultaneously, it also requires a multidisciplinary team, which should include an infectious diseases physician, a clinical pharmacist with infectious diseases training, infection control professionals, hospital epidemiologist, a clinical microbiologist and an information specialist. However, for antimicrobial stewardship (AMS) programs to be successful, they must address the specific needs of individual institutions, must be built on available resources, the limitations and advantages of each institution, and the available staffing and technological infrastructure.