Overall and cause-specific excess mortality in HIV-positive persons compared with the general population: Role of HCV coinfection

We aimed to estimate overall and cause-specific excess mortality of HIV-positive patients compared with the general population, and to assess the effect of risk factors.We included patients aged >19 years, recruited from January 1, 2004 to May 31, 2014 in Cohort of the Spanish Network on HIV/AIDS Research. We used generalized linear models with Poisson error structure to model excess mortality rates.In 10,340 patients, 368 deaths occurred. Excess mortality was 0.82 deaths per 100 person-years for all-cause mortality, 0.11 for liver, 0.08 for non-AIDS-defining malignancies (NADMs), 0.08 for non-AIDS infections, and 0.02 for cardiovascular-related causes. Lower CD4 count and higher HIV viral load, lower education, being male, and over 50 years were predictors of overall excess mortality. Short-term (first year follow-up) overall excess hazard ratio (eHR) for subjects with AIDS at entry was 3.71 (95% confidence interval [CI] 2.66, 5.19) and 1.37 (95% CI 0.87, 2.15) for hepatitis C virus (HCV)-coinfected; medium/long-term eHR for AIDS at entry was 0.90 (95% CI 0.58, 1.39) and 3.83 (95% CI 2.37, 6.19) for HCV coinfection. Liver excess mortality was associated with low CD4 counts and HCV coinfection. Patients aged ≥50 years and HCV-coinfected showed higher NADM excess mortality, and HCV-coinfected patients showed increased non-AIDS infections excess mortality.Overall, liver, NADM, non-AIDS infections, and cardiovascular excesses of mortality associated with being HIV-positive were found, and HCV coinfection and immunodeficiency played significant roles. Differential short and medium/long-term effects of AIDS at entry and HCV coinfection were found for overall excess mortality.The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006 and RD12/0017/0018) as part of the Plan Nacional R+D+I and cofinanced by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER)S

Low CD4/CD8 ratio is associated with increased morbidity and mortality in late and non-late presenters: results from a multicentre cohort study, 2004–2018

Background To study whether the association between the CD4/CD8 ratio variation over time and the development of clinical outcomes vary in late presenters (CD4 count 0.4, CD4/CD8 ratio 0.4, regardless of the late presentation status. Conclusions A low CD4/CD8 measured over time is associated with increased risk of morbidity and mortality in people living with HIV independently of their late presentation status. These data support the prognostic role of CD4/CD8 over time and can help defining a subgroup of patients who need closer monitoring to avoid comorbidities

Late presentation for HIV remains a major health issue in Spain: Results from a multicenter cohort study, 2004-2018.

With the purpose of reducing the well-known negative impact of late presentation (LP) on people living with HIV (PLWH), guidelines on early HIV diagnosis were published in 2014 in Spain, but since then no data on LP prevalence have been published. To estimate prevalence and risk factors of LP and to evaluate their impact on the development of clinical outcomes in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) during 2004-2018. CoRIS is an open prospective multicenter cohort of PLWH, adults, naive to ART at entry. LP was defined as HIV diagnosis with CD4 count ≤350 cells/μL or an AIDS defining event (ADE). Multivariable Poisson regression models were used to estimate both prevalence ratios (PR) for the association of potential risk factors with LP and Incidence rate ratios (IRRs) for its impact on the development of the composite endpoint (first ADE, first serious non-AIDS event [SNAE] or overall mortality). 14,876 individuals were included. Overall, LP prevalence in 2004-2018 was 44.6%. Risk factors for LP included older age, having been infected through injection drug use or heterosexual intercourse, low educational level and originating from non-European countries. LP was associated with an increased risk of the composite endpoint (IRR: 1.34; 95%CI 1.20, 1.50), ADE (1.39; 1.18, 1.64), SNAE (1.22; 1.01, 1.47) and mortality (1.71; 1.41, 2.08). LP remains a health problem in Spain, mainly among certain populations, and is associated with greater morbidity and mortality. Public policies should be implemented to expand screening and early diagnosis of HIV infection, for a focus on those at greatest risk of LP.RR received funds from Gilead for this work.The funders had no role in study design,data collection and analysis, decision to publish,or preparation of the manuscript.S

Effectiveness of the combination elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COB/TFV/FTC) plus darunavir among treatment-experienced patients in clinical practice: A multicentre cohort study

Background: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). Methods: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014-2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen). Results: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients (all with baseline VL ≥ 50 copies/ml) changed due to virological failure. Conclusions: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads.The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional I + D + i and cofinanced by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER)”

Effectiveness and tolerability of dolutegravir/lamivudine for the treatment of HIV-1 infection in clinical practice

Objectives: To assess the effectiveness and tolerability of dolutegravir (DTG)/lamivudine (3TC) among treatment-naive and virologically suppressed treatment-experienced individuals in the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) during the years 2018-2021. Methods: We used multivariable regression models to compare viral suppression (VS) [HIV RNA viral load (VL) <50 copies/mL] and the change in CD4 cell counts at 24 and 48 (±12) weeks after initiation with dolutegravir/lamivudine or other first-line ART regimens. Results: We included 2160 treatment-naive subjects, among whom 401 (18.6%) started with dolutegravir/lamivudine. The remaining subjects started bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (n = 949, 43.9%), DTG + FTC/tenofovir disoproxil fumarate (TDF) (n = 282, 13.1%), DTG/3TC/abacavir (ABC) (n = 255, 11.8%), darunavir (DRV)/cobicistat(COBI)/FTC/TAF (n = 147, 6.8%) and elvitegravir (EVG)/COBI/FTC/TAF (n = 126, 5.8%). At 24 and 48 weeks after starting dolutegravir/lamivudine, 91.4% and 93.8% of the subjects, respectively, achieved VS. The probability of achieving VS with dolutegravir/lamivudine was not significantly different compared with any other regimen at 24 or 48 weeks, with the exception of a lower chance of achieving VS at 24 weeks for DRV/COBI/FTC/TAF (adjusted OR: 0.47; 95% CI: 0.30-0.74) compared with dolutegravir/lamivudine.For the analysis of treatment-experienced virally suppressed subjects we included 1456 individuals who switched to dolutegravir/lamivudine, among whom 97.4% and 95.5% maintained VS at 24 and 48 weeks, respectively. During the first 48 weeks after dolutegravir/lamivudine initiation, 1.0% of treatment-naive and 1.5% of treatment-experienced subjects discontinued dolutegravir/lamivudine due to an adverse event. Conclusions: In this large multicentre cohort, effectiveness and tolerability of dolutegravir/lamivudine were high among treatment-naive and treatment-experienced subjects.This work was supported by (i) the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional I + D + i and co-financed by Instituto de Salud Carlos III-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), and (ii) ViiV Healthcare. The funders did not play any decision making role in the design, execution, analysis or reporting of the research.S

Healthcare utilization of patients accessing an African national treatment program

<p>Abstract</p> <p>Background</p> <p>The roll-out of antiretroviral therapy (ART) in Africa will have significant resource implications arising from its impact on demand for healthcare services. Existing studies of healthcare utilization on HAART have been conducted in the developed world, where HAART is commenced when HIV illness is less advanced.</p> <p>Methods</p> <p>This paper describes healthcare utilization from program entry by treatment-naïve patients in a peri-urban settlement in South Africa. Treatment criteria included a CD4 cell count <200 cells/μl or an AIDS-defining illness. Data on health service utilization were collected retrospectively from the primary-care clinic and secondary and tertiary referral hospitals. Hospital visits were reviewed to determine the clinical reason for each visit.</p> <p>Results</p> <p>212 patients were followed for a median of 490 days. Outpatient visits per 100 patient years of observation (PYO), excluding scheduled primary-care follow-up, fell from 596 immediately prior to ART to 334 in the first 48 weeks on therapy and 245 thereafter. Total inpatient time fell from 2,549 days per 100 PYO pre-ART to 476 in the first 48 weeks on therapy and 73 thereafter. This fall in healthcare utilization occurred at every level of care. The greatest causes of utilization were tuberculosis, cryptococcal meningitis, HIV-related neoplasms and adverse reactions to stavudine. After 48 weeks on ART demand reverted to primarily non-HIV-related causes.</p> <p>Conclusion</p> <p>Utilization of both inpatient and outpatient hospital services fell significantly after commencement of ART for South African patients in the public sector, with inpatient demand falling fastest. Earlier initiation might reduce early on-ART utilization rates.</p

Task sharing in Zambia: HIV service scale-up compounds the human resource crisis

BACKGROUND: Considerable attention has been given by policy makers and researchers to the human resources for health crisis in Africa. However, little attention has been paid to quantifying health facility-level trends in health worker numbers, distribution and workload, despite growing demands on health workers due to the availability of new funds for HIV/AIDS control scale-up. This study analyses and reports trends in HIV and non-HIV ambulatory service workloads on clinical staff in urban and rural district level facilities. METHODS: Structured surveys of health facility managers, and health services covering 2005-07 were conducted in three districts of Zambia in 2008 (two urban and one rural), to fill this evidence gap. Intra-facility analyses were conducted, comparing trends in HIV and non-HIV service utilisation with staff trends. RESULTS: Clinical staff (doctors, nurses and nurse-midwives, and clinical officers) numbers and staff population densities fell slightly, with lower ratios of staff to population in the rural district. The ratios of antenatal care and family planning registrants to nurses/nurse-midwives were highest at baseline and increased further at the rural facilities over the three years, while daily outpatient department (OPD) workload in urban facilities fell below that in rural facilities. HIV workload, as measured by numbers of clients receiving antiretroviral treatment (ART) and prevention of mother to child transmission (PMTCT) per facility staff member, was highest in the capital city, but increased rapidly in all three districts. The analysis suggests evidence of task sharing, in that staff designated by managers as ART and PMTCT workers made up a higher proportion of frontline service providers by 2007. CONCLUSIONS: This analysis of workforce patterns across 30 facilities in three districts of Zambia illustrates that the remarkable achievements in scaling-up HIV/AIDS service delivery has been on the back of sustained non-HIV workload levels, increasing HIV workload and stagnant health worker numbers. The findings are based on an analysis of routine data that are available to district and national managers. Mixed methods research is needed, combining quantitative analyses of routine health information with follow-up qualitative interviews, to explore and explain workload changes, and to identify and measure where problems are most acute, so that decision makers can respond appropriately. This study provides quantitative evidence of a human resource crisis in health facilities in Zambia, which may be more acute in rural areas

Co-production: towards a utopian approach

This article outlines how co-production might be understood as a utopian method, which both attends to and works against dominant inequalities. It suggests that it might be positioned ‘within, against, and beyond’ current configurations of power in academia and society more broadly. It develops this argument by drawing on recent research funded through the UK’s Connected Communities programme, led by the Arts and Humanities Research Council; and by attending to arguments from the field of Utopian Studies. It explores particular issues of power and control within the field of co-production, acknowledging that neoliberalism both constrains and co-opts such practice; and explores methodological and infrastructural issues such that its utopian potential might be realised

Proteomic Profile Associated With Loss of Spontaneous Human Immunodeficiency Virus Type 1 Elite Control

[Background] Elite controllers (ECs) spontaneously control plasma human immunodeficiency virus type 1 (HIV-1) RNA without antiretroviral therapy. However, 25% lose virological control over time. The aim of this work was to study the proteomic profile that preceded this loss of virological control to identify potential biomarkers.[Methods] Plasma samples from ECs who spontaneously lost virological control (transient controllers [TCs]), at 2 years and 1 year before the loss of control, were compared with a control group of ECs who persistently maintained virological control during the same follow-up period (persistent controllers [PCs]). Comparative plasma shotgun proteomics was performed with tandem mass tag (TMT) isobaric tag labeling and nanoflow liquid chromatography coupled to Orbitrap mass spectrometry.[Results] Eighteen proteins exhibited differences comparing PC and preloss TC timepoints. These proteins were involved in proinflammatory mechanisms, and some of them play a role in HIV-1 replication and pathogenesis and interact with structural viral proteins. Coagulation factor XI, α-1-antichymotrypsin, ficolin-2, 14-3-3 protein, and galectin-3-binding protein were considered potential biomarkers.[Conclusions] The proteomic signature associated with the spontaneous loss of virological control was characterized by higher levels of inflammation, transendothelial migration, and coagulation. Galectin-3 binding protein could be considered as potential biomarker for the prediction of virological progression and as therapeutic target in ECs.This work was supported by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos Europeos para el Desarrollo Regional (grant numbers PI10/02635, PI13/00796, and PI16/00503 to F. V.; PI12/02283, PI16/00684, and CPII014/00025 to E. R.-M.; FI14/00431 to L. T.-D.; and CP14/00198 to N. R.); Programa de Suport als Grups de Recerca (grant numbers 2017SGR948 and 2014SGR250); the Gilead Fellowship Program (grant numbers GLD14/293 and GLD17/00299); the Red de Investigación en Sida (grant numbers RD12/0017/0005, RD16/0025/0006, RD12/0017/0029, RD16/0025/0020, and RD12/0017/0031, RD16/0025/0013); Ministerio de Economia y Competitividad, Spain (grant number SAF2015-66193-R); and the Spanish Ministry of Education (grant number FPU13/02451 to B. D. M). E. R.-M. is supported by Consejería de Salud y Bienestar Social of Junta de Andalucía through the Nicolás Monardes program (C-0032/17). F. V. is supported by a grant from the Programa de Intensificación de Investigadores, Instituto de Salud Carlos III (grant numbers INT11/240, INT12/282, and INT15/226). A. R. is supported by a grant from the Acció Instrumental d’incorporació de científics i tecnòlegs (PERIS SLT002/16/00101), Departament de Salut, Generalitat de Catalunya.Peer reviewe

Comparison of dynamic monitoring strategies based on CD4 cell counts in virally suppressed, HIV-positive individuals on combination antiretroviral therapy in high-income countries:a prospective, observational study

Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individuals. We compared dynamic monitoring strategies based on time-varying CD4 cell counts in virologically suppressed HIV-positive individuals. In this observational study, we used data from prospective studies of HIV-positive individuals in Europe (France, Greece, the Netherlands, Spain, Switzerland, and the UK) and North and South America (Brazil, Canada, and the USA) in The HIV-CAUSAL Collaboration and The Centers for AIDS Research Network of Integrated Clinical Systems. We compared three monitoring strategies that differ in the threshold used to measure CD4 cell count and HIV RNA viral load every 3-6 months (when below the threshold) or every 9-12 months (when above the threshold). The strategies were defined by the threshold CD4 counts of 200 cells per μL, 350 cells per μL, and 500 cells per μL. Using inverse probability weighting to adjust for baseline and time-varying confounders, we estimated hazard ratios (HRs) of death and of AIDS-defining illness or death, risk ratios of virological failure, and mean differences in CD4 cell count. 47 635 individuals initiated an antiretroviral therapy regimen between Jan 1, 2000, and Jan 9, 2015, and met the eligibility criteria for inclusion in our study. During follow-up, CD4 cell count was measured on average every 4·0 months and viral load every 3·8 months. 464 individuals died (107 in threshold 200 strategy, 157 in threshold 350, and 200 in threshold 500) and 1091 had AIDS-defining illnesses or died (267 in threshold 200 strategy, 365 in threshold 350, and 459 in threshold 500). Compared with threshold 500, the mortality HR was 1·05 (95% CI 0·86-1·29) for threshold 200 and 1·02 (0·91·1·14) for threshold 350. Corresponding estimates for death or AIDS-defining illness were 1·08 (0·95-1·22) for threshold 200 and 1·03 (0·96-1·12) for threshold 350. Compared with threshold 500, the 24 month risk ratios of virological failure (viral load more than 200 copies per mL) were 2·01 (1·17-3·43) for threshold 200 and 1·24 (0·89-1·73) for threshold 350, and 24 month mean CD4 cell count differences were 0·4 (-25·5 to 26·3) cells per μL for threshold 200 and -3·5 (-16·0 to 8·9) cells per μL for threshold 350. Decreasing monitoring to annually when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL does not worsen the short-term clinical and immunological outcomes of virally suppressed HIV-positive individuals. However, more frequent virological monitoring might be necessary to reduce the risk of virological failure. Further follow-up studies are needed to establish the long-term safety of these strategies. National Institutes of Healt