Post-mortem findings in Spanish patients with COVID-19; a special focus on superinfections.

Introduction: Whole-body autopsies may be crucial to understand coronavirus disease 2019 (COVID-19) pathophysiology. We aimed to analyze pathological findings in a large series of full-body autopsies, with a special focus on superinfections. Methods: This was a prospective multicenter study that included 70 COVID-19 autopsies performed between April 2020 and February 2021. Epidemiological, clinical and pathological information was collected using a standardized case report form. Results: Median (IQR) age was 70 (range 63.75-74.25) years and 76% of cases were males. Most patients (90%,) had at least one comorbidity prior to COVID-19 diagnosis, with vascular risk factors being the most frequent. Infectious complications were developed by 65.71% of the patients during their follow-up. Mechanical ventilation was required in most patients (75.71%) and was mainly invasive. In multivariate analyses, length of hospital stay and invasive mechanical ventilation were significantly associated with infections (p = 0.036 and p = 0.013, respectively). Necropsy findings revealed diffuse alveolar damage in the lungs, left ventricular hypertrophy in the heart, liver steatosis and pre-infection arteriosclerosis in the heart and kidneys. Conclusion: Our study confirms the main necropsy histopathological findings attributed to COVID-19 in a large patient series, while underlining the importance of both comorbid conditions and superinfections in the pathology.

HIV medical care interruption among people living with HIV in Spain, 2004-2020.

OBJECTIVE: We estimated the incidence rate of HIV medical care interruption (MCI) and its evolution over a 16-year-period, and identified associated risk factors among HIV-positive individuals from the Cohort of the Spanish AIDS Research Network in 2004-2020. DESIGN: We included antiretroviral-naive individuals aged at least 18 years at enrolment, recruited between January 1, 2004, and August 30, 2019, and followed-up until November 30, 2020. METHODS: Individuals with any time interval of at least 15 months between two visits were defined as having a MCI. We calculated the incidence rate (IR) of having at least one MCI and used multivariable Poisson regression models to identify associated risk factors. RESULTS: Of 15 274 individuals, 5481 (35.9%) had at least one MCI. Of those, 2536 (46.3%) returned to HIV care after MCI and 3753 (68.5%) were lost to follow-up at the end of the study period. The incidence rate (IR) of MCI was 7.2/100 person-years (py) [95% confidence interval (CI): 7.0-7.4]. The annual IR gradually decreased from 20.5/100 py (95% CI: 16.4-25.6) in 2004 to 4.9/100 py (95% CI: 4.4-5.5) in 2014, a slight increase was observed between 2015 and 2018, reaching 9.3/100 py (95% CI: 8.6-10.2) in 2019. Risk factors for MCI included younger age, lower educational level, having contracted HIV infection through injecting drug use or heterosexual intercourse, having been born outside of Spain, and CD4 + cell count >200 cell/µl, viral load <100 000 and co-infection with hepatitis C virus at enrolment. CONCLUSIONS: Around a third of individuals had at least one MCI during the follow-up. Identified predictors of MCI can help health workers to target and support most vulnerable individuals.

Healthcare outcomes in patients with HIV infection at a tertiary hospital during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has affected the care of patients with other diseases. Difficulty in access to healthcare during these months has been especially relevant for persons with HIV infection (PWH). This study therefore sought to ascertain the clinical outcomes and effectiveness of the measures implemented among PWH in a region with one of the highest incidence rates in Europe. METHODS: Retrospective, observational, pre-post intervention study to compare the outcomes of PWH attended at a high-complexity healthcare hospital from March to October 2020 and during the same months across the period 2016-2019. The intervention consisted of home drug deliveries and preferential use of non face-to-face consultations. The effectiveness of the measures implemented was determined by reference to the number of emergency visits, hospitalisations, mortality rate, and percentage of PWH with viral load >50copies, before and after the two pandemic waves. RESULTS: A total of 2760 PWH were attended from January 2016 to October 2020. During the pandemic, there was a monthly mean of 106.87 telephone consultations and 2075 home deliveries of medical drugs dispensed to ambulatory patients. No statistically significant differences were found between the rate of admission of patients with COVID-HIV co-infection and that of the remaining patients (1172.76 admissions/100,000 population vs. 1424.29, p=0.401) or in mortality (11.54% vs. 12.96%, p=0.939). The percentage of PWH with viral load >50copies was similar before and after the pandemic (1.20% pre-pandemic vs. 0.51% in 2020, p=0.078). CONCLUSION: Our results show that the strategies implemented during the first 8 months of the pandemic prevented any deterioration in the control and follow-up parameters routinely used on PWH. Furthermore, they contribute to the debate about how telemedicine and telepharmacy can fit into future healthcare models.

Healthcare outcomes in patients with HIV infection at a tertiary hospital during the COVID-19 pandemic / Resultados en la atención a pacientes con infección por VIH en un hospital terciario durante la pandemia COVID-19

Background: The COVID-19 pandemic has affected the care of patients with other diseases. Difficulty in access to healthcare during these months has been especially relevant for persons with HIV infection (PWH). This study therefore sought to ascertain the clinical outcomes and effectiveness of the measures implemented among PWH in a region with one of the highest incidence rates in Europe. Methods: Retrospective, observational, pre-post intervention study to compare the outcomes of PWH attended at a high-complexity healthcare hospital from March to October 2020 and during the same months across the period 2016–2019. The intervention consisted of home drug deliveries and preferential use of non face-to-face consultations. The effectiveness of the measures implemented was determined by reference to the number of emergency visits, hospitalisations, mortality rate, and percentage of PWH with viral load >50copies, before and after the two pandemic waves. Results: A total of 2760 PWH were attended from January 2016 to October 2020. During the pandemic, there was a monthly mean of 106.87 telephone consultations and 2075 home deliveries of medical drugs dispensed to ambulatory patients. No statistically significant differences were found between the rate of admission of patients with COVID-HIV co-infection and that of the remaining patients (1172.76 admissions/100,000 population vs. 1424.29, p=0.401) or in mortality (11.54% vs. 12.96%, p=0.939). The percentage of PWH with viral load >50copies was similar before and after the pandemic (1.20% pre-pandemic vs. 0.51% in 2020, p=0.078). Conclusion: Our results show that the strategies implemented during the first 8 months of the pandemic prevented any deterioration in the control and follow-up parameters routinely used on PWH. Furthermore, they contribute to the debate about how telemedicine and telepharmacy can fit into future healthcare models.(AU)

Introducción: La pandemia causada por el SARS-CoV-2 ha afectado a la atención de pacientes con otras enfermedades. La dificultad en el acceso a la asistencia sanitaria durante estos meses es especialmente relevante en las personas con infección por VIH (PCV). El objetivo del estudio fue conocer los resultados clínicos y la efectividad de las medidas implementadas en PCV en una de las regiones con mayor incidencia de Europa. Métodos: Estudio observacional retrospectivo, pre-postintervención, comparando los resultados de PCV atendidos en un hospital de alta complejidad entre marzo-octubre de 2020 y el mismo periodo de 2016 a 2019. La intervención consistió en el envío a domicilio de medicamentos y la realización preferente de consultas no presenciales. La efectividad de las medidas implementadas se determinó por el número de visitas a urgencias, hospitalizaciones, mortalidad y porcentaje de PCV con carga viral>50 copias antes y después de 2 olas pandémicas. Resultados: Se atendieron 2.760 PCV entre enero de 2016 y octubre de 2020. Durante la pandemia se realizaron una media mensual de 106,87 consultas telefónicas y 2.075 envíos a domicilio de medicamentos de dispensación ambulatoria. No se encontraron diferencias estadísticamente significativas en la frecuentación de pacientes con coinfección COVID-VIH respecto al resto (1.172,76 ingresos/100.000 habitantes vs. 1.424,29, p=0,401), ni en su mortalidad (11,54 vs. 12,96%, p=0,939). El porcentaje de PCV con carga viral>50 copias fue similar antes y después de la pandemia (1,20% prepandemia vs. 0,51% en 2020, p=0,078). Conclusión: Nuestros resultados revelan que las estrategias implementadas durante los 8 primeros meses de pandemia han evitado el deterioro en parámetros de control y seguimiento empleados habitualmente en PCV. Además, contribuyen a la reflexión sobre el encaje de la telemedicina y telefarmacia en modelos asistenciales futuros.(AU)

Healthcare outcomes in patients with HIV infection at a tertiary hospital during the COVID-19 pandemic.

Background: The COVID-19 pandemic has affected the care of patients with other diseases. Difficulty in access to healthcare during these months has been especially relevant for persons with HIV infection (PWH). This study therefore sought to ascertain the clinical outcomes and effectiveness of the measures implemented among PWH in a region with one of the highest incidence rates in Europe. Methods: Retrospective, observational, pre-post intervention study to compare the outcomes of PWH attended at a high-complexity healthcare hospital from March to October 2020 and during the same months across the period 2016-2019. The intervention consisted of home drug deliveries and preferential use of non face-to-face consultations. The effectiveness of the measures implemented was determined by reference to the number of emergency visits, hospitalisations, mortality rate, and percentage of PWH with viral load >50 copies, before and after the two pandemic waves. Results: A total of 2760 PWH were attended from January 2016 to October 2020. During the pandemic, there was a monthly mean of 106.87 telephone consultations and 2075 home deliveries of medical drugs dispensed to ambulatory patients. No statistically significant differences were found between the rate of admission of patients with COVID-HIV co-infection and that of the remaining patients (1172.76 admissions/100,000 population vs. 1424.29, p = 0.401) or in mortality (11.54% vs. 12.96%, p = 0.939). The percentage of PWH with viral load >50 copies was similar before and after the pandemic (1.20% pre-pandemic vs. 0.51% in 2020, p = 0.078). Conclusion: Our results show that the strategies implemented during the first 8 months of the pandemic prevented any deterioration in the control and follow-up parameters routinely used on PWH. Furthermore, they contribute to the debate about how telemedicine and telepharmacy can fit into future healthcare models.

Introducción: La pandemia causada por el SARS-CoV-2 ha afectado a la atención de pacientes con otras enfermedades. La dificultad en el acceso a la asistencia sanitaria durante estos meses es especialmente relevante en las personas con infección por VIH (PCV). El objetivo del estudio fue conocer los resultados clínicos y la efectividad de las medidas implementadas en PCV en una de las regiones con mayor incidencia de Europa. Métodos: Estudio observacional retrospectivo, pre-postintervención, comparando los resultados de PCV atendidos en un hospital de alta complejidad entre marzo-octubre de 2020 y el mismo periodo de 2016 a 2019. La intervención consistió en el envío a domicilio de medicamentos y la realización preferente de consultas no presenciales. La efectividad de las medidas implementadas se determinó por el número de visitas a urgencias, hospitalizaciones, mortalidad y porcentaje de PCV con carga viral > 50 copias antes y después de 2 olas pandémicas. Resultados: Se atendieron 2.760 PCV entre enero de 2016 y octubre de 2020. Durante la pandemia se realizaron una media mensual de 106,87 consultas telefónicas y 2.075 envíos a domicilio de medicamentos de dispensación ambulatoria. No se encontraron diferencias estadísticamente significativas en la frecuentación de pacientes con coinfección COVID-VIH respecto al resto (1.172,76 ingresos/100.000 habitantes vs. 1.424,29, p = 0,401), ni en su mortalidad (11,54 vs. 12,96%, p = 0,939). El porcentaje de PCV con carga viral > 50 copias fue similar antes y después de la pandemia (1,20% prepandemia vs. 0,51% en 2020, p = 0,078). Conclusión: Nuestros resultados revelan que las estrategias implementadas durante los 8 primeros meses de pandemia han evitado el deterioro en parámetros de control y seguimiento empleados habitualmente en PCV. Además, contribuyen a la reflexión sobre el encaje de la telemedicina y telefarmacia en modelos asistenciales futuros.

Long-term Evaluation of Residual Viremia in a Clinical Trial of Dolutegravir Plus Lamivudine as Maintenance Treatment for Participants With and Without Prior Lamivudine Resistance.

In this pilot clinical trial, we evaluated rates of residual replication in persons without lamivudine resistance-associated mutations in proviral DNA population sequencing who switched to dolutegravir plus lamivudine. After 144 weeks, there was no signal of changes in residual viremia based on qualitative detection methods, irrespective of past lamivudine resistance. Clinical Trials Registration. NCT03539224.

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 < 350/µL or AIDS event at enrolment) or advanced presenters (CD4 count < 200/µL or AIDS event at enrolment). METHODS: We included ART-naïve adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) enrolled between January 2004 up to November 2018 and with at least 6 months of follow-up. We used extended Cox proportional hazard models to estimate the hazard ratios (HRs) for the association between CD4/CD8 ratio over time and a composite endpoint of the occurrence of the first AIDS event, first serious non-AIDS event or overall mortality occurring from 6 months after enrolment. HRs in non-late, late and advanced presenters were obtained by including an interaction term between late presentation status and CD4/CD8 ratio over time. RESULTS: Of 10,018 participants, 55.6% were late presenters and 26.5% were advanced presenters. Compared with CD4/CD8 ratio > 0.4, CD4/CD8 ratio ≤ 0.4 over time was associated with an increased risk of experiencing the composite endpoint in non-late (HR 1.90; 95%CI 1.48, 2.43), late (HR 1.94; 1.46, 2.57) and advanced presenters (HR 1.72; 1.26, 2.34). Similarly, CD4/CD8 ratio ≤ 0.4 over time was associated with a higher risk of developing an AIDS event (HR 3.31; 2.23, 4.93 in non-late; HR 2.75; 1.78, 4.27 in late and HR 2.25; 1.34, 3.76 in advanced presenters) or serious non-AIDS event (HR 1.39; 0.96, 2.02 in non-late, HR 1.62; 1.10, 2.40 in late and HR 1.49; 0.97, 2.29 in advanced presenters) as well as with a higher risk of overall mortality (HR 1.49; 0.92, 2.41 in non-late, HR 1.80; 1.04, 3.11 in late and HR 1.61; 0.92, 2.83 in advanced presenters) compared to CD4/CD8 > 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.

Incidence and Severity of SARS-CoV-2 Infection in HIV-Infected Individuals During the First Year of the Pandemic.

BACKGROUND: We aim to investigate the infection rate, the clinical characteristics and outcomes of COVID-19-disease in a cohort of people living with HIV in Madrid (Spain), during the first year of pandemics. SETTING: Observational single-center study, in which we included all HIV-infected patients (aged ≥ 18 years) with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as of February 28, 2021, at the Hospital Universitario 12 de Octubre. METHODS: Confirmed disease was defined as any patient with a positive antigen test, reverse transcriptase polymerase chain reaction, or serology for SARS-CoV-2. We compared the characteristics of patients with mild disease (asymptomatic included) with those with moderate or severe disease (requiring admission). RESULTS: Of 2344 HIV-infected patients, 158 (82.9% male; median age, 46.5 years) were diagnosed with SARS-CoV-2 (infection rate, 6.74%; 95% confidence interval, 5.79 to 7.83). Thirty-nine individuals (24.7%) had moderate or severe disease, 43.7% had mild disease, and 31.6% were asymptomatic. Hypertension (23.4%) and obesity (15.8%) were the most prevalent comorbidities; 12.7% had at least 2 comorbidities. One hundred forty-five patients (97.3%) had RNA-HIV viral load of <50 copies per milliliter, and only 3 had CD4 cell count of <200 cells per cubic millimeter before infection. Of those admitted to hospital, 59% required oxygen support and 15.4%, invasive mechanical ventilation. Five patients died. None of the patient taking tenofovir-disoproxil-fumarate required admission. In the multivariate analysis, age remained as the only independent factor for moderate-severe disease (odds ratio, 1.09; 95% confidence interval 1.04 to 1.14; P < 0.001). CONCLUSIONS: People living with HIV are at risk of severe SARS-CoV-2 infection. Age was the only variable with an independent association with moderate-severe disease, after adjusting by comorbidities and other factors.

Management of Comorbidities in Treated HIV Infection: A Long Way to Go: HIV, comorbidities and aging.

Modern ART has now achieved the goal of maintaining HIV RNA suppression with minimum drug-related toxicities. Indeed, in high-income settings, the main health issues in adult people living with HIV (PLWH) today are diseases not directly associated with HIV. These conditions have become the central topic of discussion in HIV clinical forums. While they are common in the general population and typically associated with the aging process, their burden, diagnosis, clinical course and subsequent therapy alongside treated HIV infection exhibit specific features. Currently, we are confronted with the formidable challenge of normalizing the health of PLWH and creating a more comprehensive HIV management program. Here, we compile the opinions of a joint effort of 30 HIV specialists who reviewed the literature and debated the latest major challenges in the field of HIV-associated comorbidities and delineated future strategies to fully normalize health in HIV. Six key questions are answered and developed, such as the relevance of comorbidities in the management of HIV-infected patients, their drivers, management, prevention strategies, and possible evolution in the future.

Detection of archived lamivudine-associated resistance mutations in virologically suppressed, lamivudine-experienced HIV-infected adults by different genotyping techniques (GEN-PRO study).

BACKGROUND: Previously selected lamivudine resistance-associated mutations (RAMs) may remain archived within the proviral HIV-DNA. OBJECTIVES: To evaluate the ability of proviral DNA genotyping to detect lamivudine RAMs in HIV-1 virologically suppressed participants; the correlation between Sanger and next generation sequencing (NGS); and predictive factors for detection of lamivudine RAMs in proviral DNA. METHODS: Cross-sectional study of participants on stable antiretroviral therapy and suppressed for ≥1 year. Analysis of proviral DNA was performed by Sanger sequencing in whole blood and by NGS in PBMCs. RESULTS: We analysed samples from 102 subjects (52 with and 50 without lamivudine RAMs in historical plasma RNA-genotypes). Among participants with previous lamivudine resistance, Sanger sequencing detected RAMs in 26.9%. Detection rates significantly increased using NGS: 47.9%, 64.6%, 75% and 87.5% with the 20%, 10%, 5% and 1% thresholds, respectively. As for participants without historical lamivudine resistance, Sanger detected the RAMs in 1/49 (2%), and NGS (5% threshold) in 8/45 (17.8%). Multivariate models fitted to the whole population revealed that having a history of lamivudine resistance was a risk factor for detection of lamivudine RAMs by NGS. Among participants with historical lamivudine resistance, multivariate analysis showed that a longer time since HIV diagnosis was associated with persistence of archived mutations by NGS at thresholds of >10% [OR 1.10 (95% CI: 1.00-1.24)] and >5% [OR 1.16 (95% CI: 1.02-1.32)]. CONCLUSIONS: Proviral DNA Sanger sequencing does not detect the majority of historical lamivudine RAMs. NGS increases the sensitivity of detection at lower thresholds, although the relevance of these minority populations with lamivudine RAMs needs further evaluation.

Determinants of HIV-1 Late Presentation in Patients Followed in Europe.

To control the Human Immunodeficiency Virus (HIV) pandemic, the World Health Organization (WHO) set the 90-90-90 target to be reached by 2020. One major threat to those goals is late presentation, which is defined as an individual presenting a TCD4+ count lower than 350 cells/mm3 or an AIDS-defining event. The present study aims to identify determinants of late presentation in Europe based on the EuResist database with HIV-1 infected patients followed-up between 1981 and 2019. Our study includes clinical and socio-demographic information from 89851 HIV-1 infected patients. Statistical analysis was performed using RStudio and SPSS and a Bayesian network was constructed with the WEKA software to analyze the association between all variables. Among 89,851 HIV-1 infected patients included in the analysis, the median age was 33 (IQR: 27.0-41.0) years and 74.4% were males. Of those, 28,889 patients (50.4%) were late presenters. Older patients (>56), heterosexuals, patients originated from Africa and patients presenting with log VL >4.1 had a higher probability of being late presenters (p < 0.001). Bayesian networks indicated VL, mode of transmission, age and recentness of infection as variables that were directly associated with LP. This study highlights the major determinants associated with late presentation in Europe. This study helps to direct prevention measures for this population.

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

OBJECTIVES: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Late presentation for HIV impairs immunological but not virological response to antiretroviral treatment.

OBJECTIVES: The aim of this study was to examine the impact of late presentation (CD4+ cell count <350 cells/µl or an AIDS-defining event) on effectiveness and safety of initial antiretroviral therapy (ART) and to evaluate whether treatment response depends on first-line ART regimen in late presenters. DESIGN: ART-naive adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) starting triple ART between 2010 and 2018. METHODS: We used multivariable models to assess differences in viral suppression (viral load <50 copies/ml), immunological response (change in CD4+ cell count, CD4% (>29%) and CD4/CD8 normalization (>0.4 and >1) multiple T-cell marker recovery (MTMR): CD4+ cell count more than 500 cells/µl and CD4% >29% and CD4/CD8 >1), and treatment discontinuation due to adverse events (TDAE) at 48 weeks from ART initiation. RESULTS: Out of 8002 participants, 48.7% were late presenters. Of them, 45.8% initiated ART with a NNRTI- (mostly TDF/FTC/EFV), 33.9% with a protease inhibitor (mostly TDF/FTC+boosted DRV) and 20.3% with an INI-based regimen (mostly ABC/3TC/DTG). At 48 weeks, late presenters had similar viral suppression, but worse immunological response, than non-late presenters with no difference on TDAE. Late presenters initiating with NNRTI-based regimens were more likely to achieve viral suppression than those starting with INI-based, due to the higher chance of achieving viral suppression observed with TDF/FTC/RPV compared to ABC/3TC/DTG. Initial treatment with NNRTI or protease inhibitor based showed similar immunological response than the INI-based regimens, which showed lower rates of TDAE than NNRTI- and protease inhibitor based regimens. CONCLUSION: Despite safety and effectiveness of initial ART in terms of viral suppression, late presenters may not experience complete immunological response. In late presenters, effectiveness and safety depends on both the class and the specific first-line ART regimen.

Cryptococcal infection in HIV-infected patients with CD4+ T-cell counts under 100/µL diagnosed in a high-income country: a multicentre cohort study.

OBJECTIVES: The World Health Organization recommends routinely screening HIV-infected patients with CD4+ T-cell counts <100/µL for cryptococcal infection to prevent cryptococcal meningitis (CM), based on studies in Sub-Saharan Africa where the prevalence of positive cryptococcal antigen (CrAg+) is ≥ 3% in this subgroup. Data about such prevalence in Spain are unavailable and rare in other European countries. Thus, the Spanish AIDS Study Group guidelines do not recommend routinely screening. We aim to determine the prevalence and outcomes of cryptococcal infection in this subgroup of patients in Spain. METHODS: We determined CrAg using a lateral flow assay in banked plasma from participants in the cohort of the Spanish AIDS Research Network. Eligible patients had CD4+ T-cell counts ≤100/µL at the time of plasma collection and a follow-up >4 weeks, unless they died. RESULTS: We included 576 patients from June 2004 to December 2017. Of these, 43 were CrAg+ for an overall prevalence of 7.5%. There were no differences depending on birthplace. The CrAg+ was independently associated with a higher mortality at eight weeks (hazard ratio (HR) 5.36, 95% confidence interval (CI) 1.46-19.56) and 6 months (HR 3.12, 95% CI 1.19-8.21). CM was reported in 10 of the 43 CrAg+ patients. There were no cases among negatives. Five patients had CM when the plasma was collected and five developed it during the follow-up. The number of subjects needed to screen to anticipate the diagnosis of one CM case was 114. CONCLUSIONS: The CrAg+ prevalence among HIV-infected patients with CD4+ T-cell counts ≤100/µL diagnosed in Spain, both immigrants and native-born Spanish, is >7%. Consequently, the Spanish AIDS Study Group guidelines have to be updated and recommend routine screening for cryptococcal infection in these patients. Future studies should explore whether this recommendation could be firmly applied to other European populations.

Long-term efficacy of dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: Week 96 results of ART-PRO pilot study.

BACKGROUND: In the ART-PRO pilot trial there were no virological failures through 48 weeks of treatment with dolutegravir plus lamivudine in suppressed individuals with and without archived lamivudine resistance-associated mutations (RAMs) detected through next-generation sequencing (NGS) but without evidence of lamivudine RAMs in baseline proviral DNA population sequencing. OBJECTIVES: To present 96 week results from ART-PRO. METHODS: Open-label, single-arm pilot trial. At baseline, all participants switched to dolutegravir plus lamivudine. Participants were excluded if proviral DNA population genotyping detected lamivudine RAMs. To detect resistance minority variants, proviral DNA NGS was retrospectively performed from baseline samples. For this analysis the efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 96. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. RESULTS: Forty-one participants were included, 21 with lamivudine RAMs in historical plasma RNA genotypes. Baseline proviral DNA NGS detected lamivudine RAMs (M184V/I and/or K65R/E/N) above a 5% threshold in 71.4% (15/21) and 15% (3/20) of participants with and without history of lamivudine resistance, respectively. At 96 weeks, 90.2% of participants achieved the efficacy endpoint. Between week 48 and 96 there was one discontinuation due to consent withdrawal and no discontinuations related to adverse events. Two participants had a transient viral rebound, both re-suppressed on dolutegravir plus lamivudine. Through week 96, there were no virological failures. CONCLUSIONS: In this pilot trial, dolutegravir plus lamivudine maintained virological suppression at 96 weeks despite historical lamivudine resistance and persisting archived minority lamivudine RAMs.

Prolonged administration of maraviroc reactivates latent HIV in vivo but it does not prevent antiretroviral-free viral rebound.

Human immunodeficiency virus (HIV) remains incurable due to latent viral reservoirs established in non-activated CD4 T cells that cannot be eliminated via antiretroviral therapy. Current efforts to cure HIV are focused on identifying drugs that will induce viral gene expression in latently infected cells, commonly known as latency reversing agents (LRAs). Some drugs have been shown to reactivate latent HIV but do not cause a reduction in reservoir size. Therefore, finding new LRAs or new combinations or increasing the round of stimulations is needed to cure HIV. However, the effects of these drugs on viral rebound after prolonged treatment have not been evaluated. In a previous clinical trial, antiretroviral therapy intensification with maraviroc for 48 weeks caused an increase in residual viremia and episomal two LTR-DNA circles suggesting that maraviroc could reactivate latent HIV. We amended the initial clinical trial to explore additional virologic parameters in stored samples and to evaluate the time to viral rebound during analytical treatment interruption in three patients. Maraviroc induced an increase in cell-associated HIV RNA during the administration of the drug. However, there was a rapid rebound of viremia after antiretroviral therapy discontinuation. HIV-specific T cell response was slightly enhanced. These results show that maraviroc can reactivate latent HIV in vivo but further studies are required to efficiently reduce the reservoir size.

Brief Report: Durable Suppression and Low Rate of Virologic Failure 3 Years After Switch to Dolutegravir + Rilpivirine 2-Drug Regimen: 148-Week Results From the SWORD-1 and SWORD-2 Randomized Clinical Trials.

BACKGROUND: The SWORD trials showed that in participants who achieved virologic suppression taking 3-drug or 4-drug regimens, switching to the 2-drug regimen dolutegravir plus rilpivirine was noninferior in maintaining HIV-1 RNA <50 copies/mL at the week 48 primary endpoint. We present pooled week 148 analysis results from both studies. SETTING: SWORD-1: 65 centers, 13 countries; SWORD-2: 60 centers, 11 countries. METHODS: SWORD-1 and SWORD-2 are identical, open-label, phase III studies. Participants with screening HIV-1 RNA <50 copies/mL for ≥6 months; no prior virologic failure; and no documented resistance-associated major protease inhibitor, integrase inhibitor, nucleoside reverse transcriptase inhibitor (NRTI), or non-NRTI mutations or integrase resistance-associated substitution R263K were randomly assigned 1:1 to switch to once-daily dolutegravir 50 mg plus rilpivirine 25 mg on day 1 (early-switch group) or to continue their current antiretroviral regimen and, if virologically suppressed at week 48, switch to dolutegravir plus rilpivirine at week 52 (late-switch group) until week 148. RESULTS: Using snapshot algorithm at week 148, 432 of 513 (84%) early-switch participants (148 weeks of exposure) and 428 of 477 (90%) late-switch participants (96 weeks of exposure) maintained HIV-1 RNA <50 copies/mL. Eleven participants (1%) on dolutegravir plus rilpivirine met the confirmed virologic withdrawal criterion through week 148 (early-switch group, n = 8; late-switch group, n = 3) with no integrase resistance identified. Non-NRTI resistance-associated mutations were identified in 6 participants (<1%). Drug-related adverse events (grades 2-4) were observed in 31 (6%) early-switch and 16 (3%) late-switch participants. Significant improvements in bone biomarkers were observed. Significant improvements were observed in renal biomarkers in participants taking tenofovir disoproxil fumarate pre-switch. CONCLUSION: Switching to the 2-drug regimen dolutegravir plus rilpivirine maintained virologic suppression for a high proportion of participants through 3 years, with low rates of virologic failure and a well-tolerated safety profile.

Sustained virological response at week 12 after interferon-free therapy as criterion for HCV cure definition: Validation in a real-life cohort of HIV-coinfected patients / Validación de la respuesta viral sostenida en la semana 12 tras tratamiento con pautas libres de interferón para la confirmación de la curación de la infección por VHC en una cohorte de pacientes con coinfección por VIH

INTRODUCTION: Sustained virological response (SVR) 12 weeks after the end-of-therapy (EOT) has been correlated with SVR24 for HCV-monoinfection. We aim to validate SVR12 as criterion for definition of HCV cure in HIV-coinfected patients treated with all-oral direct-acting antivirals (DAA). METHODS: Prospectively observational study including HIV/HCV-coinfected subjects who received DAA and had HCV-RNA measures at weeks 12 and 24 after EOT. Every patient who took ≥1 drug dose was analyzed. RESULTS: DAA were prescribed to 423 patients, of whom 387 had HCV-RNA measures both at weeks 12 and 24 after EOT. SVR12 was confirmed in 379/387 patients, while SVR24 was confirmed in 377/387 subjects. The positive-predictive-value (PPV) of SVR12 for SVR24 was 99.5% (95%CI: 98.1-99.9). One of the recurrences was clinically suspected to be a late relapse. CONCLUSIONS: SVR12 has a high PPV for HCV cure in HIV/HCV-coinfection, though further follow-up could be necessary for those with deeper immunosuppression

INTRODUCCIÓN: En monoinfección por VHC, se ha demostrado correlación entre la respuesta viral sostenida (RVS) 12 semanas posterapia antiviral con la RVS24. Proponemos validar la RVS12 como criterio de curación en sujetos coinfectados por VIH/VHC tratados con antivirales de acción directa (AAD). MÉTODOS: Estudio observacional prospectivo con pacientes coinfectados VIH/VHC, tratados con AAD y con determinación de ARN-VHC en semanas 12 y 24 posterapia. Se analizó todo sujeto que tomó ≥1 dosis de AAD. RESULTADOS: Se prescribieron AAD a 423 sujetos: 387 tenían determinación de ARN-VHC en semanas 12 y 24 posterapia. Se confirmó RVS12 en 379/387 pacientes y RVS24 en 377/387. El valor predictivo positivo (VPP) de RVS12 para RVS24 fue del 99,5% (IC 95%: 98,1-99,9). Una recurrencia se interpretó clínicamente como recidiva tardía. CONCLUSIONES: La RVS12 tiene un elevado VPP para predecir curación de la infección por VHC en pacientes VIH-positivo, aunque podrían ser necesarios más controles en aquéllos más inmunosuprimidos

Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO).

BACKGROUND: We investigated the efficacy of a switch to dolutegravir plus lamivudine in aviremic individuals without evidence of persistent lamivudine resistance-associated mutations in baseline proviral DNA population sequencing. METHODS: Open-label, single-arm, 48-week pilot trial. HIV-1 infected adults, naïve to integrase inhibitors, with CD4+ above 350 cell/µL and fewer than 50 HIV-1 RNA copies per mL the year prior to study entry switched to dolutegravir plus lamivudine. Participants were excluded if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. To detect resistance minority variants, proviral DNA next-generation sequencing was retrospectively performed from baseline samples. Primary efficacy endpoint was proportion of participants with fewer than 50 HIV-1 RNA copies per mL at week 48. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. ART-PRO is registered with ClinicalTrials.gov, NCT03539224. FINDINGS: 41 participants switched to dolutegravir plus lamivudine, 21 with lamivudine resistance mutations in historical plasma genotypes. Baseline next-generation sequencing detected lamivudine resistance mutations (M184V/I and/or K65R/E/N) over a 5% threshold in 15/21 (71·4%) and 3/20 (15%) of participants with and without history of lamivudine resistance, respectively. At week 48, 92·7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine. There were 28 drug-related adverse events, only one leading to discontinuation. INTERPRETATION: In this pilot trial, dolutegravir plus lamivudine was effective in maintaining virologic control despite past historical lamivudine resistance and presence of archived lamivudine resistance-associated mutations detected by next generation sequencing. Further studies are needed to confirm our results. FUNDING: Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III PI16/00837-PI16/00678.