Associations of modern initial antiretroviral drug regimens with all-cause mortality in adults with HIV in Europe and North America: a cohort study

Background: Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018. Methods: This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data. Findings: 62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30–48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6–4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15–1·94), elvitegravir (1·86, 1·43–2·42), rilpivirine (1·99, 1·49–2·66), darunavir (1·62, 1·33–1·98), and efavirenz (2·12, 1·60–2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013–15 and 2016–18. Rates of virological suppression were higher for dolutegravir than other third drugs. Interpretation: This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality. Funding: US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council

CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE.

BACKGROUND: Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. METHODS AND FINDINGS: Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/µl, 0.81 (0.71-0.92) for counts 200 to <350 cells/µl, 0.74 (0.66-0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. CONCLUSIONS: Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl

y CD4 Cell Count and the Risk of AIDS or Death in HIV-Infected Adults on Combination Antiretroviral Therapy with a Suppressed Viral Load: A Longitudinal Cohort Study from COHERE

Background Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. Methods and Findings Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50–500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30–0.40) for counts <200 cells/µl, 0.81 (0.71–0.92) for counts 200 to <350 cells/µl, 0.74 (0.66–0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92–0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. Conclusions Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl

Skin manifestations of Pseudomonas aeruginosa infections

Purpose of review Pseudomonas aeruginosa is an opportunistic pathogen with considerable morbidity and mortality, particularly in vulnerable hosts. Skin manifestations are common, either representing local inoculation or secondary skin seeding following bloodstream infections. As patients with various predisposing conditions are expanding, we sought to review the most recent published evidence regarding epidemiology, risk factors and diagnosis of skin manifestations of P. aeruginosa. Recent findings New data exist on epidemiology and diagnosis of skin infections; systemic infections are impacted by multidrug-resistance issues and host immune status. Summary Green nail syndrome, toe web infection, hot tub folliculitis, hot hand-foot infection and external otitis are the most common infections originating from the skin per se. Local treatments are the cornerstone and prognosis is favorable in immunocompetent hosts. Ecthyma gangrenosum and P. aeruginosa subcutaneous nodules are usually associated with bloodstream infections and occur primarily in immunocompromised hosts. Necrotizing skin and soft tissue infections occur in diabetic, alcoholic and immunocompromised patients; management requires a multidisciplinary team with surgical approach. Burn wound infections may also be challenging, requiring a specialized team. In all the four latter types of P. aeruginosa skin infections portending significant morbidity and mortality, systemic antibiotics are an integral part of the treatment. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved

The role of HIV-1 DNA as an additional marker of HIV-1 infection

After the infusion of HIV-1 virus into a host cell, RNA is reverse transcribed to dsDNA, which persists intracellular to the infected cell in a variety of forms. Numerous in-house assays have been developed for the quantification of the different cellular HIV-1 DNA forms; these implement conventional or real-time PCR methodology. In this review we discuss recent findings about the longitudinal monitoring of cell-associated HIV-1 DNA in naïve and pre-treated patients, as a marker for clinical progression, treatment initiation and long-term success of HAART. These findings underline the importance of monitoring HIV-1 DNA in clinical practice, in addition to HIV-RNA and CD4+ T Cell counts, for the better assessment of HIV-treatment and disease progression. The lack of a standardized real-time PCR assay is major impediment to more wide-spread HIV-1 DNA monitoring. © 2009 Bentham Science Publishers Ltd

HBV-DNA levels predict overall mortality in HIV/HBV coinfected individuals

The coinfection of Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) has been associated with increased death rates. However, the relevant research has mostly relied on serologic HBV testing [HBV surface antigen (HBsAg)]. The aim of this work was to explore the relationship of HBV viraemia with overall mortality among HIV/HBV coinfected individuals. The analysis included 1,609 HIV seropositives of a previously described cohort (1984-2003) with limited exposure to tenofovir (12%) and a median follow-up of approximately 5 years. Those with persistent expression of HBsAg were further tested for HBV-DNA. The data were analyzed using Poisson regression models. Totally, 101 participants were chronic carriers of HBsAg (6.28%). Of these, 81 were tested for HBV-DNA. The median HBV-DNA levels were 3.81 log (base-10) International Units (IU)/ml. A third (31%) of those tested for HBV-DNA had received tenofovir. Before developing acquired immune deficiency syndrome (AIDS), the adjusted incidence rate ratio (IRR) for all-cause mortality of coinfected patients with HBV viraemia above the median value versus the HIV monoinfected group was 3.44 [95% confidence interval (CI): 1.05-11.27]. Multivariable regressions in the coinfected group only (n=81) showed that one log-10 increase in HBV-DNA levels was associated with an elevated risk for death (IRR: 1.24, 95%CI: 1.03-1.49). HBV-DNA levels predict overall mortality in the setting of HIV/HBV coinfection, especially during the period before developing AIDS, and could thus help prioritize needs and determine the frequency of medical monitoring. © 2016 Wiley Periodicals, Inc

Tracking missed opportunities for an early HIV diagnosis in a population of people living with HIV with known time of infection

Purpose The goal of 90-90-90 first requires the expansion of access to HIV testing. Our aim was to record frequencies of HIV indicator conditions (ICs) and identify missed opportunities for an early HIV diagnosis. Methods We retrospectively identified ICs in a population of 231 people living with HIV with known infection dates who attended our clinic. The study population was divided into four groups: (1) those self-tested pre-emptively (47/231, 20.3%), (2) those offered targeted testing based on risk factors (67/231, 29%), (3) those tested after an IC (73/231, 31.6%) and (4) those who were not offered testing after an IC (44/231, 19%). HIV acquisition dates were estimated by molecular clock analysis. Results A total of 169 healthcare contacts (HCCs) were recorded. The most frequent HCC was mononucleosis-like syndrome (20.1%), unexplained weight loss (10.7%) and STIs (10.1%). AIDS-defining conditions were detected in 11.8%. Only 62.4% (73/117) of those with an IC were offered testing after their first HCC. Patients in group 4 had statistically significant delay in diagnosis compared with group 3 (109.1 weeks (IQR 56.4-238.6) vs 71.6 weeks (IQR 32.3-124.6)). The proportion of patients diagnosed as late presenters in each group was: (1) 16/47 (34%), (2) 37/67 (55.2%), (3) 43/73 (58.9%) and (4) 27/44 (61.4%) (p=0.027). Conclusions Our study uses a combination of molecular and clinical data and shows evidence that late presentation occurs in a high proportion of patients even in the presence of an IC. Given that risk-based targeted testing has low coverage, IC-guided testing provides a reasonable alternative to facilitate earlier HIV diagnosis and to improve late diagnosis across Europe and globally.