Excess Weight Gain With Integrase Inhibitors and Tenofovir Alafenamide: What Is the Mechanism and Does It Matter?

Numerous studies have detected a greater likelihood of excess weight gain with specific antiretrovirals (ARVs), particularly tenofovir alafenamide and integrase inhibitors, as compared with other agents and classes. The long-term implications and potential reversibility for individuals who have experienced substantial ARV-associated weight accumulation remain poorly understood. Furthermore, the underlying mechanism remains controversial: Is the explanation mitochondrial toxicity and weight suppression from the older agents or direct effects of the newer drugs on appetite, adipocytes, or other unintended targets? This review discusses proposed mechanisms and evidence to date and argues that the question about mechanism is highly clinically relevant because it carries significant implications for ARV management.

A Dual-Platform Point-of-Care Test for Neurosyphilis Diagnosis.

Background: The diagnosis of neurosyphilis relies on cerebrospinal fluid (CSF) abnormalities (pleocytosis, elevated protein) and CSF-Venereal Disease Research Laboratory (VDRL) test. In resource-limited settings, the CSF-VDRL test may not be widely available.

Methods: We optimized a commercial immunochromatographic strip test, the DPP Chembio syphilis assay, for performance with CSF and tested centrifuged CSF samples of 71 patients with syphilis (35 with neurosyphilis and 36 without neurosyphilis).

Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naïve and -experienced, virologically-suppressed adults living with HIV-1.

Background: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917).

Objective: To describe a Week 96 pre-planned subgroup analysis of D/C/F/TAF arms by demographic characteristics (age ≤/>50 years, gender, black/non-black race), and baseline clinical characteristics (AMBER: viral load [VL], CD4 count, WHO clinical stage, HIV-1 subtype and antiretroviral resistance; EMERALD: prior virologic failure [VF], antiretroviral experience, screening boosted protease inhibitor [PI], and boosting agent).

Methods: Patients in D/C/F/TAF and control arms could continue on/switch to D/C/F/TAF in a single-arm, open-label extension phase after Week 48 until Week 96.

Real-world efficacy of direct acting antiviral therapies in patients with HIV/HCV.

The advent of direct-acting antiviral (DAA) therapies has dramatically transformed HCV treatment, with most recent trials demonstrating high efficacy rates (>90%) across all genotypes and special populations, including patients with HIV/HCV coinfection. The efficacy rates of HCV treatment are nearly identical between patients with HCV monofection and patients with HIV/HCV coinfection; however, there are limited studies to compare real-world efficacy with efficacy observed in clinical trials. Using a database from HIV clinics across the United States (US), we identified 432 patients with HIV/HCV coinfection who completed DAA therapy from January 1, 2014 to March 31, 2017 and were assessed for efficacy.

HIV/HCV therapy with ledipasvir/sofosbuvir after randomized switch to emtricitabine-tenofovir alafenamide-based single-tablet regimens.

Introduction: Guidelines advocate the treatment of HCV in all HIV/HCV co-infected individuals. The aim of this randomized, open-label study (ClinicalTrials.gov identifier: NCT02707601; https://clinicaltrials.

Atherosclerotic Cardiovascular Disease Risk Profile of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate.

Background: In human immunodeficiency virus (HIV) treatment, tenofovir alafenamide (TAF) is associated with greater increases in all fasting cholesterol subgroups compared with tenofovir disoproxil fumarate (TDF). Because lipid abnormalities may contribute to cardiovascular morbidity and mortality, cardiovascular risk assessment is integral to routine HIV care. This post hoc study evaluates the impact of lipid changes on predicted atherosclerotic cardiovascular disease (ASCVD) risk and statin eligibility in treatment-naive adults living with HIV treated with TAF or TDF.

Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in a Rapid-Initiation Model of Care for Human Immunodeficiency Virus Type 1 Infection: Primary Analysis of the DIAMOND Study.

Background: Most guidelines recommend rapid treatment initiation for patients with newly diagnosed human immunodeficiency virus type 1 (HIV-1) infection, but prospective US data are limited. The DIAMOND (NCT03227861) study using darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a phase 3 prospective study evaluating efficacy/safety of a single-tablet regimen in a rapid-initiation model of care.

Methods: Adults aged ≥18 years began D/C/F/TAF ≤14 days from diagnosis without screening/baseline results; as results became available, participants not meeting predefined safety/resistance stopping rules continued.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-experienced, virologically suppressed patients with HIV-1: subgroup analyses of the phase 3 EMERALD study.

Background: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a once-daily, single-tablet regimen for treatment of HIV-1 infection. The efficacy/safety of switching to D/C/F/TAF versus continuing boosted protease inhibitor (bPI) + emtricitabine/tenofovir disoproxil fumarate (control) were demonstrated in a phase 3, randomized study (EMERALD) of treatment-experienced, virologically suppressed adults through week 48. The objective of this analysis was to evaluate EMERALD outcomes across subgroups of patients based on demographic characteristics, prior treatment experience, and baseline antiretroviral regimen.

Pharmacokinetics of tenofovir monoester and association with intracellular tenofovir diphosphate following single-dose tenofovir disoproxil fumarate.

Background: Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported.

Methods: Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus® ingestible sensor.

Daclatasvir and sofosbuvir with ribavirin for 24 weeks in chronic hepatitis C genotype-3-infected patients with cirrhosis: a Phase III study (ALLY-3C).

Background: Optimal treatment for patients with HCV genotype-3 infection and liver cirrhosis remains a medical priority. Daclatasvir+sofosbuvir and ribavirin is a recommended option for such patients, but clinical trial data are lacking for treatment >16 weeks.

Methods: This was a single-arm, Phase III study of daclatasvir+sofosbuvir+ribavirin for 24 weeks in patients with compensated cirrhosis and HCV genotype-3 infection.

Contribution of Liver Fibrosis and Microbial Translocation to Immune Activation in Persons Infected With HIV and/or Hepatitis C Virus.

Background: The independent contributions of microbial translocation and liver fibrosis to immune activation in human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV)-infected persons are unclear.

Methods: Multivariable linear regression was used to evaluate whether intestinal fatty acid binding protein (I-FABP: a marker of gut epithelial integrity) and transient elastography-measured liver fibrosis might mediate the association of HIV and HCV with the soluble CD14 (sCD14) level in 120 individuals with HIV and HCV coinfection, 262 with HIV monoinfection, 72 with HCV monoinfection, and 170 without infection.

Results: Coinfected individuals, HIV-monoinfected individuals, and HCV-monoinfected individuals had 37%, 21%, and 12% higher sCD14 levels, respectively, than uninfected individuals, after multivariable adjustment.

A Randomized, Open-Label Trial to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Darunavir in Treatment-Experienced HIV-1-Infected Adults.

Background: HIV-infected, treatment-experienced adults with a history of prior resistance and regimen failure can be virologically suppressed but may require multitablet regimens associated with lower adherence and potential resistance development.

Methods: We enrolled HIV-infected, virologically suppressed adults with 2-class to 3-class drug resistance and at least 2 prior regimen failures into this phase 3, open-label, randomized study. The primary endpoint was the percentage of participants with HIV-1 RNA <50 copies per milliliter at week 24 [Food and Drug Administration (FDA) snapshot algorithm].

A matched cross-sectional study of the association between circulating tissue factor activity, immune activation and advanced liver fibrosis in hepatitis C infection.

Background: Tissue factor (TF) is a protein that mediates the initiation of the coagulation cascade. TF expression is increased in patients with poorly-controlled HIV, and may be associated with increased immune activation that leads to cardiovascular morbidity. The role of TF in immune activation in liver disease in hepatitis C virus (HCV)-monoinfection and HIV/HCV-coinfection has not been explored.

Simplification from twice-daily to once-daily darunavir/ritonavir in a randomized trial among HIV-infected persons with HIV-1 RNA suppression on antiretroviral therapy.

Background: DRIVESHAFT is a randomized, open-label, 48-week clinical trial that examined virological outcomes and safety of antiretroviral simplification among virologically suppressed, treatment-experienced HIV-infected patients switching from darunavir/ritonavir (DRV/r) twice-daily-based regimens to a once-daily DRV/r component.

Methods: HIV-infected adults with a stable antiretroviral regimen including DRV/r 600/100 mg twice daily plus a minimum of two other antiretrovirals, <2 historical DRV-associated mutations and HIV RNA<40 copies/ml for at least 12 weeks prior to entry were eligible. Participants were randomized 1:1 to switch DRV/r to 800/100 mg once daily or maintain their current regimen.

Characterization of CD4⁺ T-cell immune activation and interleukin 10 levels among HIV, hepatitis C virus, and HIV/HCV-coinfected patients.

Background: HIV/hepatitis C virus (HCV)-coinfected patients have accelerated liver disease compared with HCV monoinfection. In HIV-positive patients with viral suppression, data comparing inflammatory cytokines and immune activation between HIV/HCV coinfection with chronic hepatitis C (CHC) to HIV/HCV-seropositive patients with cleared HCV are limited.

Methods: Fifty-nine age- and sex-matched patients were stratified: (1) HIV monoinfection (n = 15); (2) HCV monoinfection with CHC (n = 15); (3) HIV/HCV coinfection with CHC (n = 14); and (4) HIV/HCV seropositive with cleared HCV (n = 15).

Phaeomycotic cysts caused by Phoma species.

Phoma species are primarily phytopathogens which have been reported to sporadically cause human disease. We report a patient with phaeohyphomycotic cysts caused by Phoma species, which were initially mistaken for ganglions.

Early development of non-hodgkin lymphoma following initiation of newer class antiretroviral therapy among HIV-infected patients - implications for immune reconstitution.

Background: In the HAART era, the incidence of HIV-associated non-Hodgkin lymphoma (NHL) is decreasing. We describe cases of NHL among patients with multi-class antiretroviral resistance diagnosed rapidly after initiating newer-class antiretrovirals, and examine the immunologic and virologic factors associated with potential IRIS-mediated NHL.

Methods: During December 2006 to January 2008, eligible HIV-infected patients from two affiliated clinics accessed Expanded Access Program antiretrovirals of raltegravir, etravirine, and/or maraviroc with optimized background.

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere.

Factors associated with newly diagnosed HIV among persons with concomitant sexually transmitted diseases.

Objective: We evaluated Illinois and Chicago Departments of Public Health surveillance databases to determine risk factors associated with newly diagnosed HIV among persons with bacterial sexually transmitted diseases (STDs).

Methods: Test results for Chlamydia, gonorrhea, early syphilis (primary, secondary, and early latent), and HIV from public health clinics in Illinois in 2002 were merged with demographic and behavioral survey data collected during patient visits. STD was defined as any positive non-HIV result.

Outbreak of bloodstream infection with the mold Phialemonium among patients receiving dialysis at a hemodialysis unit.

Background: Molds are a rare cause of disseminated infection among dialysis patients.

Objective: We evaluated a cluster of intravascular infections with the mold Phialemonium among patients receiving hemodialysis at the same facility in order to identify possible environmental sources and prevent further infection.

Design: Environmental assessment and case-control study.

Clinical manifestations of human monkeypox influenced by route of infection.

Background: In April 2003, an outbreak of monkeypox occurred in the United States following the importation of monkeypox virus (MPXV)-infected animals in a consignment of exotic pets from West Africa. Transmission of the virus to non-African captive species, including prairie dogs, preceded human disease.

Methods: We evaluated the influence of the route of infection on clinical illness for persons with confirmed and probable cases of human monkeypox.

Myocarditis Outbreak among Adults, Illinois, 2003.

An outbreak of myocarditis occurred among adults in Illinois in 2003. Diagnostic testing of myocardial tissues from 3 patients and comprehensive tests for enterovirus and adenovirus of other specimens from patients were inconclusive. Appropriate specimen collection from patients with idiopathic cardiomyopathy and further enhancement of diagnostic techniques are needed.

Clinical characteristics of human monkeypox, and risk factors for severe disease.

Background: Human monkeypox is an emerging smallpox-like illness that was identified for the first time in the United States during an outbreak in 2003. Knowledge of the clinical manifestations of monkeypox in adults is limited, and clinical laboratory findings have been unknown.

Methods: Demographic information; medical history; smallpox vaccination status; signs, symptoms, and duration of illness, and laboratory results (hematologic and serum chemistry findings) were extracted from medical records of patients with a confirmed case of monkeypox in the United States.

Vaccination coverage survey versus administrative data in the assessment of mass yellow fever immunization in internally displaced persons--Liberia, 2004.

Yellow fever (YF) is a mosquito-borne vaccine-preventable disease with high mortality. In West Africa, low population immunity increases the risk of epidemic transmission. A cluster survey was conducted to determine the effectiveness of a mass immunization campaign using 17D YF vaccine in internally displaced person (IDP) camps following a reported outbreak of YF in Liberia in February 2004.