Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//μL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location.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). This study was funded by ViiV Healthcare. ViiV Healthcare was given the opportunity to review a preliminary version of this manuscript for factual accuracy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors are solely responsible for final content and interpretation of the results.S

USO DE RECURSOS SANITARIOS Y COSTES ASOCIADOS AL TRATAMIENTO ANTIRRETROVIRAL DE PRIMERA LÍNEA EN ESPAÑA EN LA ERA DE LOS INHIBIDORES DE LA INTEGRASA

Introducción: El objetivo fue evaluar el uso de recursos sanitarios y costes asociados durante el primer año de tratamiento antirretroviral (TAR) con las pautas de primera línea prescritas más frecuentemente en los pacientes de la cohorte de la Red Española de Investigación en SIDA  en la era de los inhibidores de la integrasa. Métodos: Utilizamos un modelo de evaluación de costes en el que el consumo de recursos sanitarios derivados de iniciar tratamiento con cada pauta se estimó utilizando el método Delphi de dos rondas, mediante cuestionario estructurado, en un panel de 35 expertos en VIH. El coste total incluía los costes de TAR, del manejo clínico y del manejo de efectos adversos (EA). Se aplicó la perspectiva del pagador (Sistema Nacional de Salud), considerando solo costes directos. Resultados: En el análisis por intención de tratar, el coste anual varió entre 8.501 € para TDF/FTC/EFV y 12.840 € para TDF/FTC+RAL. De media, el coste farmacológico supone el 87,6% del coste total, variando entre 83,8 % para TDF/FTC/EFV y 91,1% para TDF/FTC+RAL. El coste del manejo clínico supone el 11,5% del coste total (8,6% para TDF/FTC+RAL y 13,9% para ABC/3TC/DTG). Sólo el 0,9% del coste de la pauta se debe al manejo de EA, más elevados con TDF/FTC/EFV (2,6%) y TDF/FTC+DRV/r (1,1%). Conclusión: El coste para el sistema sanitario del primer año de TAR se debe, fundamentalmente, al precio de los fármacos. Las pautas con menor coste fueron TDF/FTC/EFV, TDF/FTC/RPV y ABC/3TC/DTG, siendo TDF/FTC/EVG/COBI y TDF/FTC+RAL las de coste superior

USO DE RECURSOS SANITARIOS Y COSTES ASOCIADOS AL TRATAMIENTO ANTIRRETROVIRAL DE PRIMERA LÍNEA EN ESPAÑA EN LA ERA DE LOS INHIBIDORES DE LA INTEGRASA

Introducción: El objetivo fue evaluar el uso de recursos sanitarios y costes asociados durante el primer año de tratamiento antirretroviral (TAR) con las pautas de primera línea prescritas más frecuentemente en los pacientes de la cohorte de la Red Española de Investigación en SIDA  en la era de los inhibidores de la integrasa. Métodos: Utilizamos un modelo de evaluación de costes en el que el consumo de recursos sanitarios derivados de iniciar tratamiento con cada pauta se estimó utilizando el método Delphi de dos rondas, mediante cuestionario estructurado, en un panel de 35 expertos en VIH. El coste total incluía los costes de TAR, del manejo clínico y del manejo de efectos adversos (EA). Se aplicó la perspectiva del pagador (Sistema Nacional de Salud), considerando solo costes directos. Resultados: En el análisis por intención de tratar, el coste anual varió entre 8.501 € para TDF/FTC/EFV y 12.840 € para TDF/FTC+RAL. De media, el coste farmacológico supone el 87,6% del coste total, variando entre 83,8 % para TDF/FTC/EFV y 91,1% para TDF/FTC+RAL. El coste del manejo clínico supone el 11,5% del coste total (8,6% para TDF/FTC+RAL y 13,9% para ABC/3TC/DTG). Sólo el 0,9% del coste de la pauta se debe al manejo de EA, más elevados con TDF/FTC/EFV (2,6%) y TDF/FTC+DRV/r (1,1%). Conclusión: El coste para el sistema sanitario del primer año de TAR se debe, fundamentalmente, al precio de los fármacos. Las pautas con menor coste fueron TDF/FTC/EFV, TDF/FTC/RPV y ABC/3TC/DTG, siendo TDF/FTC/EVG/COBI y TDF/FTC+RAL las de coste superior

Identification and validation of clinical phenotypes with prognostic implications in patients admitted to hospital with COVID-19: a multicentre cohort study

REIPI-SEIMC COVID-19 group and COVID@HULP group.[Background] The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality.[Methods] In this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model.[Findings] Three distinct phenotypes were derived in the derivation cohort (n=2667)—phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])—and reproduced in the internal validation cohort (n=1368)—phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4–4·3) for patients with phenotype A, 30·5% (28·5–32·6) for patients with phenotype B, and 60·7% (53·7–67·2) for patients with phenotype C (log-rank test p<0·0001). The predicted phenotypes in the internal validation cohort and external validation cohort showed similar mortality rates to the assigned phenotypes (internal validation cohort: 5·3% [95% CI 3·4–8·1] for phenotype A, 31·3% [28·5–34·2] for phenotype B, and 59·5% [48·8–69·3] for phenotype C; external validation cohort: 3·7% [2·0–6·4] for phenotype A, 23·7% [21·8–25·7] for phenotype B, and 51·4% [41·9–60·7] for phenotype C).[Interpretation] Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated.[Funding] Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.Peer reviewe

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) &lt; 50 copies/ml and &lt; 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (&lt; 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 &lt; 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL &lt; 50 copies/ml, 85.7% and 80.0% had VL &lt; 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL &lt; 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL &lt; 50 copies/ml and 69.2% and 68.2% had VL &lt; 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)”

Impact of late presentation of HIV infection on short-, mid- and long-term mortality and causes of death in a multicenter national cohort: 2004–2013

SummaryObjectivesTo analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004–2013).MethodsCox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 < 350 cells/ml or AIDS.ResultsOf 7165 new HIV diagnoses, 46.9% (CI95%:45.7–48.0) were LP, 240 patients died.First-year mortality was the highest (aHRLP.vs.nLP = 10.3[CI95%:5.5–19.3]); between 1 and 4 years post-diagnosis, aHRLP.vs.nLP = 1.9(1.2–3.0); and >4 years, aHRLP.vs.nLP = 1.5(0.7–3.1).First-year's main cause of death was HIV/AIDS (73%); and malignancies among those surviving >4 years (32%). HIV/AIDS-related deaths were more likely in LP (59.2% vs. 25.0%; p < 0.001). LP declined from 55.9% (2004–05) to 39.4% (2012–13), and reduced in 46.1% in men who have sex with men (MSM) and 37.6% in heterosexual men, but increased in 22.6% in heterosexual women.Factors associated with LP: sex (ORMEN.vs.WOMEN = 1.4[1.2–1.7]); age (OR31–40.vs.<30 = 1.6[1.4–1.8], OR41–50.vs.<30 = 2.2[1.8–2.6], OR>50.vs.<30 = 3.6[2.9–4.4]); behavior (ORInjectedDrugUse.vs.MSM = 2.8[2.0–3.8]; ORHeterosexual.vs.MSM = 2.2[1.7–3.0]); education (ORPrimaryEducation.vs.University = 1.5[1.1–2.0], ORLowerSecondary.vs.University = 1.3[1.1–1.5]); and geographical origin (ORSub-Saharan.vs.Spain = 1.6[1.3–2.0], ORLatin-American.vs.Spain = 1.4[1.2–1.8]).ConclusionsLP is associated with higher mortality, especially short-term- and HIV/AIDS-related mortality. Mid-term-, but not long-term mortality, remained also higher in LP than nLP. LP decreased in MSM and heterosexual men, not in heterosexual women. The groups most affected by LP are low educated, non-Spanish and heterosexual women

Efavirenz versus boosted atazanavir-containing regimens and immunologic, virologic, and clinical outcomes: A prospective study of HIV-positive individuals

Abstract Objective: To compare regimens consisting of either ritonavir-boosted atazanavir or efavirenz and a nucleoside reverse transcriptase inhibitor (NRTI) backbone with respect to clinical, immunologic, and virologic outcomes. Design: Prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States included in the HIV-CAUSAL Collaboration. Methods: HIV-positive, antiretroviral therapy-naive, and acquired immune deficiency syndrome (AIDS)-free individuals were followed from the time they started an atazanavir or efavirenz regimen. We estimated an analog of the “intention-to-treat” effect for efavirenz versus atazanavir regimens on clinical, immunologic, and virologic outcomes with adjustment via inverse probability weighting for time-varying covariates. Results: A total of 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths) and 18,786 individuals started an efavirenz regimen (389 deaths, 825 AIDS-defining illnesses or deaths). During a median follow-up of 31 months, the hazard ratios (95% confidence intervals) were 0.98 (0.77, 1.24) for death and 1.09 (0.91, 1.30) for AIDS-defining illness or death comparing efavirenz with atazanavir regimens. The 5-year survival difference was 0.1% (95% confidence interval: −0.7%, 0.8%) and the AIDS-free survival difference was −0.3% (−1.2%, 0.6%). After 12 months, the mean change in CD4 cell count was 20.8 (95% confidence interval: 13.9, 27.8) cells/mm3 lower and the risk of virologic failure was 20% (14%, 26%) lower in the efavirenz regimens. Conclusion: Our estimates are consistent with a smaller 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with atazanavir regimens. No overall differences could be detected with respect to 5-year survival or AIDS-free survival

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

All-cause mortality after ART initiation in HIV-positive women from Europe, Sub-Saharan Africa and the Americas.

BACKGROUND Women account for over half of persons living with HIV/AIDS globally. We examined geographic variation in all-cause mortality after antiretroviral therapy (ART) for women living with HIV (WLWH) worldwide. METHODS We pooled data from WLWH at least 18 years initiating ART 2000-2014 within COHERE (Europe) and IeDEA regions (East Africa, West Africa, South Africa, North America, Latin America/Caribbean). Mortality rates were calculated at 0-3, 3-6, 6-12, 12-24 and 24-48 months after ART, and mortality rate ratios were compared with European rates with piecewise exponential parametric survival models based on Poisson regression. FINDINGS Nineteen thousand, one hundred and seventy-five WLWH (16% Europe, 47% East Africa, 13% West Africa, 19% South Africa, 1% South America, 3% North America and 2% Central America/Caribbean) were included. The highest death rates occurred 0-3 months after ART [1.51 (95% CI 1.25-1.82) per 100 person-years in Europe, 12.45 (11.30-13.73), 14.03 (13.12-15.02) and 9.44 (8.80-10.11) in East, West and South Africa, and 1.53 (0.97-2.43), 7.83 (5.44-11.27) and 17.02 (14.62-19.81) in North, South America and Central America/Caribbean, respectively] and declined thereafter. Mortality in Europe was the lowest, with regional differences greatest in the first 3 months and smaller at longer ART durations [adjusted rate ratios 24-48 months after ART: 3.63 (95% CI 3.04-4.33), 5.61 (4.84-6.51) and 3.47 (2.97-4.06) for East, West and South Africa; 2.86 (2.26-3.62), 2.42 (1.65-3.55) and 2.50 (1.92-3.26) for North, South America and Central America/Caribbean, respectively]. CONCLUSION Global variations in short-term and long-term mortality among WLWH initiating ART may inform context-specific interventions

How well are we performing the initial assessment of HIV-positive patients? Results from a multicentre cohort in Spain

[Objectives]: The aim of this study was to evaluate adherence to the recommendations of the Spanish guidelines for the initial assessment of patients with HIV infection in the multicentre Cohort of the Spanish HIV/AIDS Network (CoRIS) during the years 2004–2017.[Methods]: We calculated the percentage of patients who had each of 11 clinical and analytical recommended examinations performed in their initial evaluation. We evaluated the factors associated with not performing each examination with multivariable logistic regression models.[Results]: We included 13 612 patients in the study. In the initial assessment, CD4 count and viral load were determined in more than 98.0% of the patients. Serologies for hepatitis A, B and C and syphilis were determined in 55.8%, 66.4%, 89.8% and 81.7% of the patients, respectively. Total cholesterol and creatinine were determined in 78.7% and 78.9% of the patients, respectively. The lowest proportions of examinations were observed for blood pressure, smoking status and latent tuberculosis screening, which were performed in 43.2%, 50.6% and 53.9% of the patients, respectively. Injecting drug users and heterosexual patients (compared to men who have sex with men) and patients with a lower educational level had a higher risk of having an incomplete initial assessment for a substantial number of examinations. Latent tuberculosis screening was less likely in patients with CD4 counts < 200 cells/µL.[Conclusions]: The initial assessment of HIV‐infected patients is suboptimal for the evaluation of cardiovascular risk, smoking status, screening of syphilis and viral hepatitis, and diagnosis of latent tuberculosis: adherence to the guidelines was low for these examinations.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-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER)