Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: Prospective, non-randomized trial.

OBJECTIVES: To assess the efficacy and safety of hydroxychloroquine (HCQ) compared with no treatment in healthcare workers with mild SARS-CoV-2 infection. METHODS: Prospective, non-randomized study. All health professionals with confirmed COVID-19 between April 7 and May 6, 2020, non-requiring initial hospitalization were asked to participate. Patients who accepted treatment were given HCQ for five days (loading dose of 400mg q12h the first day followed by200mg q12h). Control group included patients with contraindications for HCQ or who rejected treatment. Study outcomes were negative conversion and viral dynamics of SARS-CoV-2, symptoms duration and disease progression. RESULT: Overall, 142 patients were enrolled: 87 in treatment group and 55 in control group. The median age was 37 years and 75% were female, with few comorbidities. There were no significant differences in time to negative conversion of PCR between both groups. The only significant difference in the probability of negative conversion of PCR was observed at day 21 (18.7%, 95%CI 2.0-35.4). The decrease of SARS-CoV-2 viral load during follow-up was similar in both groups. A non significant reduction in duration of some symptoms in HCQ group was observed. Two patients with HCQ and 4 without treatment developed pneumonia. No patients required admission to the Intensive Care Unit or died. About 50% of patients presented mild side effects of HCQ, mainly diarrhea. CONCLUSIONS: Our study failed to show a substantial benefit of HCQ in viral dynamics and in resolution of clinical symptoms in health care workers with mild COVID-19.

Real world effectiveness of standard of care triple therapy versus two-drug combinations for treatment of people living with HIV.

BACKGROUND: Since 1996, the standard of care (SOC) therapy for HIV treatment has consisted of a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug combinations (2DC) has been considered for selected patients to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase strand transfer inhibitor (INSTI)-containing triple therapy (TT) to dolutegravir- (DTG) and/or boosted protease inhibitor (bPI)-based 2DC in a large Spanish cohort of HIV patients. METHODS: A retrospective analysis was performed using data from the VACH cohort, a prospective multicentre Spanish cohort of adult HIV patients. All treatment experienced patients initiating a TT of an INSTI combined with two NRTIs or a 2DC-containing DTG and/or a bPI between 01/01/2012 and 01/06/2017 were included. The unit of analysis was patient-regimens. The overall sample analysis was complemented with two sub-analyses. The first sub-analysis focused on patients treated with a backbone plus DTG compared to those treated with DTG+ one other antiretroviral. The second sub-analysis focused on patients with HIV RNA<50 copies/mL at baseline, irrespective of the regimen used. The following endpoints were assessed: time to discontinuation for any reason, time to switch due to virologic failure, and time to switch due to toxicity (reasons for discontinuation according to clinician report in the database). Time-to-event analyses were conducted using Kaplan-Meier survival curves and Cox regression models. RESULTS: Overall 7,481 patients were included in the analysis, contributing to 9,243 patient-regimens. Patient characteristics at baseline differed among groups, with the 2DC group being significantly older and having a higher proportion of women, a longer time on ART and a higher number of previous virologic failures. Median (95% Confidence Interval [C.I.]) time to switch was 2.5 years (2.3, 2.7) in 2DC group versus 2.9 years (2.7, 3.0) in TT. Adjusted hazard ratios (95% C.I.) for discontinuation due to any reason, virologic failure and toxicity in the 2DC vs TT group were 1.29 (1.15; 1.44), 2.06 (1.54; 2.77) and 1.18 (0.94; 1.48), respectively. Results were consistent in the two sub-analyses. CONCLUSION: In this analysis, time to discontinuation and probability of remaining free of virologic failure were significantly higher in patients on INSTI-based TT compared to DTG- and/or bPI-containing 2DC, with no differences in toxicity.

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.

Screening for asymptomatic STIs in HIV-infected men who have sex with men.

We aimed to study the prevalence, characteristics and risk factors of asymptomatic sexually transmitted infections (STIs) in HIV-infected men who have sex with men (MSM). We conducted a prospective cross-sectional study, including asymptomatic HIV-infected MSM attending regular visits between December 2014 and December 2017. Of the 301 patients included, 60 patients (19.9%) presented at least one STI. The most common STI was syphilis (33 of 69 STIs), followed by chlamydia (19 of 69), gonorrhoea (10 of 69), hepatitis C virus (4 of 69) and lymphogranuloma venereum (3 of 69). Illicit drug use during sex was the only variable significantly associated with the presence of an STI on multivariate analysis (OR 2.13; 95% CI 1.17-3.89). We were unable to identify a subgroup of patients where we could potentially avoid STI screening. Our findings support current guidelines that recommend routine screening for all HIV-infected MSM regardless of their self-reported sexual history.

Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: Prospective, non-randomized trial / Eficacia y seguridad de hidroxicloroquina en profesionales sanitarios con infección leve por SARS-CoV-2: Estudio prospectivo y no aleatorio

OBJECTIVES: To assess the efficacy and safety of hydroxychloroquine (HCQ) compared with no treatment in healthcare workers with mild SARS-CoV-2 infection. METHODS: Prospective, non-randomized study. All health professionals with confirmed COVID-19 between April 7 and May 6, 2020, non-requiring initial hospitalization were asked to participate. Patients who accepted treatment were given HCQ for five days (loading dose of 400 mg q12 h the first day followed by 200 mg q12 h). Control group included patients with contraindications for HCQ or who rejected treatment. Study outcomes were negative conversion and viral dynamics of SARS-CoV-2, symptoms duration and disease progression. RESULT: Overall, 142 patients were enrolled: 87 in treatment group and 55 in control group. The median age was 37 years and 75% were female, with few comorbidities. There were no significant differences in time to negative conversion of PCR between both groups. The only significant difference in the probability of negative conversion of PCR was observed at day 21 (18.7%, 95%CI 2.0-35.4). The decrease of SARS-CoV-2 viral load during follow-up was similar in both groups. A non significant reduction in duration of some symptoms in HCQ group was observed. Two patients with HCQ and 4 without treatment developed pneumonia. No patients required admission to the Intensive Care Unit or died. About 50% of patients presented mild side effects of HCQ, mainly diarrhea. CONCLUSIONS: Our study failed to show a substantial benefit of HCQ in viral dynamics and in resolution of clinical symptoms in health care workers with mild COVID-19

OBJETIVOS: Evaluar la eficacia y seguridad de hidroxicloroquina (HCQ), en comparación con la ausencia de tratamiento en los profesionales sanitarios con infección leve por SARS-CoV-2. MÉTODOS: Estudio prospectivo y no aleatorio. Se solicitó su participación a todos los profesionales sanitarios con diagnóstico confirmado de COVID-19, entre el 7 de abril y el 6 de mayo de 2020, que no requirieron hospitalización inicial. Los pacientes que aceptaron el tratamiento recibieron HCQ durante cinco días (dosis de carga de 400 mg cada 12 h el primer día, y a continuación 200 mg cada 12 h). El grupo control incluyó pacientes con contraindicaciones de HCQ, o que rechazaron el tratamiento. Los resultados del estudio fueron conversión negativa y dinámica viral de SARS-CoV-2, duración de los síntomas y progresión de la enfermedad. RESULTADOS: En total se incluyeron 142 pacientes: 87 en el grupo de tratamiento, y 55 en el grupo control. La edad media fue de 37 años, y el 75% fueron mujeres, con pocas comorbilidades. No existieron diferencias significativas en cuanto al tiempo transcurrido hasta la conversión negativa de la PCR entre ambos grupos. La única diferencia significativa en cuanto a la probabilidad de negativización de la PCR se observó el día 21 (18,7%, IC 95% 2-35,4). El descenso de la carga viral de SARS-CoV-2 durante el seguimiento fue similar en ambos grupos. Se observó una reducción no significativa de la duración de algunos síntomas en el grupo HCQ. Dos pacientes con HCQ y cuatro sin tratamiento desarrollaron neumonía. Ningún paciente requirió ingreso en la Unidad de Cuidados Intensivos, ni hubo fallecidos. Cerca del 50% de los pacientes presentó efectos secundarios leves de HCQ, principalmente diarrea. CONCLUSIONES: Nuestro estudio no reflejó un beneficio sustancial de HCQ, en cuanto a dinámica viral y resolución de los síntomas clínicos en los profesionales sanitarios con infección leve por COVID-19

Incidencia de neoplasias en una cohorte española de pacientes con infección por el virus de la inmunodeficiencia humana / Incidence of malignancy in a Spanish cohort of patients infected by the human immunodeficiency virus

INTRODUCCIÓN: Se ha descrito una mayor incidencia de neoplasias en los pacientes con infección por VIH en comparación con la población general. PACIENTES Y MÉTODOS: Estudio observacional retrospectivo de la población infectada por VIH en seguimiento en el Hospital Vall d'Hebron (Barcelona) entre 2009 y 2017. El objetivo de este estudio fue estimar la incidencia de neoplasias en estos pacientes con infección por VIH y su supervivencia. Se comparó la incidencia ajustada por edad y sexo en dicha población con la calculada por la Red Española de Registros de Cáncer (REDECAN) en 2015. RESULTADOS: Se incluyeron 2.773 pacientes (41.238 pacientes-año). Se diagnosticaron 211 cánceres en 182 pacientes. El 78,2% de las neoplasias fueron no definitorias de sida (NNDS). La tasa global de incidencia de cáncer fue 485 neoplasias por 100.000 pacientes-año. La mortalidad a 20años en pacientes con cáncer fue del 31,2%, y del 7,8% en pacientes sin cáncer. En varones, ajustada por edad, la incidencia de neoplasias fue mayor que en la población general (978,4 vs. 641 por 100.000 pacientes-año, p < 0,001); las más frecuentes fueron carcinomas de pulmón, sarcoma de Kaposi y linfoma no Hodgkin. En mujeres, la incidencia no fue mayor a la de la población general (340,6 vs. 404,7 por 100.000 pacientes-año, p = 0,27). Las neoplasias más frecuentes fueron carcinomas pulmonares, carcinomas de cabeza y cuello, cérvix y linfoma Hodgkin. CONCLUSIONES: Los varones con infección por VIH presentaron una incidencia significativamente mayor de cáncer que la población española del mismo sexo. Los carcinomas pulmonares fueron las NNDS más frecuentes

INTRODUCTION: A higher incidence of malignancies has been described in patients with HIV infection compared to the general population. PATIENTS AND METHODS: Observational retrospective study in patients with HIV infection followed up at the Vall d'Hebron University Hospital (Barcelona, Spain) between 2009 and 2017. The objective of this research was to estimate the incidence of malignancies in HIV patients and their surveillance. Age and sex-adjusted incidence was compared to the incidence calculated by the Spanish Cancer Registry network (REDECAN) in 2015. RESULTS: We included 2,773 patients (41,238 patients-year). Two hundred and eleven malignancies were diagnosed in 182 patients. Non-AIDS defining cancers accounted for 78.2% of the malignancies. The global incidence of cancer was 485 cases per 100,000 person-years. Twenty-year mortality rate was 31.2% in patients with cancer and 7.8% in patients without cancer. In men, adjusted for age, the incidence of malignancies was higher than the incidence in the general population (978.4 vs. 641 cases per 100,000 person-years, P<.001). The most common malignancies in men were lung cancer, Kaposi sarcoma and Hodgkin lymphoma. In women, the incidence of malignancies was not higher than in the general population (340.6 vs. 404.7 cases per 100,000 person-years, P=.27). The most common malignancies among women were lung cancer, head and neck cancer, cervical cancer and Hodgkin's lymphoma. CONCLUSIONS: Men with HIV infection showed a statistically significant higher incidence of malignancies compared to the general Spanish population. Lung cancer was the most common non-AIDS defining cancer

Lipidomics Reveals Reduced Inflammatory Lipid Species and Storage Lipids after Switching from EFV/FTC/TDF to RPV/FTC/TDF: A Randomized Open-Label Trial.

HIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual species that are overlooked using conventional biochemical analyses, outperforming traditional risk equations. We aimed to compare the plasma lipidomic profile of HIV patients taking efavirenz (EFV) or rilpivirine (RPV). Patients ≥ 18 years old on EFV co-formulated with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) with HIV-RNA < 50 copies/mL for ≥6 months were randomized to continue EFV/FTC/TDF (n = 14) or switch to RPV/FTC/TDF (n =15). Lipidomic analyses conducted by mass spectrometry (MS) were performed at baseline and after 12 and 24 weeks. OWLiver® Care and OWLiver® tests were performed to estimate the presence of fatty liver disease (NAFLD). No significant differences (83% male, median age 44 years, 6 years receiving EFV/FTC/TDF, CD4+ count 740 cells/mm3, TC 207 [57 HDL-C/133 LDL-C] mg/dL, TG 117 mg/dL) were observed between the groups at baseline. Significant reductions in plasma lipids and lipoproteins but increased circulating bilirubin concentrations were observed in patients who switched to RPV/FTC/TDF. Patients on RPV/FTC/TDF showed a decrease in the global amount of storage lipids (-0.137 log2 [fold-change] EFV vs. 0.059 log2 [fold-change] RPV) but an increase in lysophosphatidylcholines (LPCs) and total steroids. Compared with EFV, RPV increased metabolites with anti-inflammatory properties and reduced the repository of specific lipotoxic lipids.

Effectiveness of boosted darunavir plus rilpivirine in patients with long-lasting HIV-1 infection: DARIL study.

BACKGROUND: The combination of boosted darunavir plus rilpivirine, once daily, could be a convenient, effective and well-tolerated two-drug regimen to achieve HIV suppression in HIV-infected patients. METHODS: Multicentre, retrospective cohort study in nine hospitals in Spain. All HIV-infected subjects starting boosted darunavir plus rilpivirine were included, irrespective of their viral load (VL). The primary objective was the percentage of patients with VL <50 copies/mL at 48 weeks. Secondary objectives included changes in CD4+ cell count, lipid profile and renal function. RESULTS: Eighty-one of 84 patients reached Week 48. Fifty-nine (70.2%) patients had VL <50 copies/mL at baseline and the rest had a median VL of 202 (IQR 98-340) copies/mL. Subjects had a median of 21 years of infection with six prior regimens. The main reasons for starting boosted darunavir plus rilpivirine were simplification (44%), kidney or bone toxicity (28.6%) and virological failure (17.9%). Historical genotypes from 47 patients showed 41 (87.2%) patients with NRTI RAMs, 21 (44.7%) with NNRTI RAMs, 12 (25.5%) with primary PI RAMs and 7 (14.9%) with integrase strand transfer inhibitor (INSTI) RAMs. One patient had low-level resistance to boosted darunavir and five patients had some resistance to rilpivirine. At 48 weeks, 71 (87.7%) patients had VL <50 copies/mL. According to undetectable or detectable baseline VL, effectiveness was 91.1% or 80%, respectively. There were four virological failures with no emergence of new RAMs. Three of these patients resuppressed viraemia while maintaining the same regimen. CONCLUSIONS: The combination of boosted darunavir plus rilpivirine has shown good effectiveness and tolerability in this cohort of pretreated patients with a long-lasting HIV infection, exposure to multiple antiretroviral regimens and prior HIV resistance.

Incidence of malignancy in a Spanish cohort of patients infected by the human immunodeficiency virus. / Incidencia de neoplasias en una cohorte española de pacientes con infección por el virus de la inmunodeficiencia humana.

INTRODUCTION: A higher incidence of malignancies has been described in patients with HIV infection compared to the general population. PATIENTS AND METHODS: Observational retrospective study in patients with HIV infection followed up at the Vall d'Hebron University Hospital (Barcelona, Spain) between 2009 and 2017. The objective of this research was to estimate the incidence of malignancies in HIV patients and their surveillance. Age and sex-adjusted incidence was compared to the incidence calculated by the Spanish Cancer Registry network (REDECAN) in 2015. RESULTS: We included 2,773 patients (41,238 patients-year). Two hundred and eleven malignancies were diagnosed in 182 patients. Non-AIDS defining cancers accounted for 78.2% of the malignancies. The global incidence of cancer was 485 cases per 100,000 person-years. Twenty-year mortality rate was 31.2% in patients with cancer and 7.8% in patients without cancer. In men, adjusted for age, the incidence of malignancies was higher than the incidence in the general population (978.4 vs. 641 cases per 100,000 person-years, P<.001). The most common malignancies in men were lung cancer, Kaposi sarcoma and Hodgkin lymphoma. In women, the incidence of malignancies was not higher than in the general population (340.6 vs. 404.7 cases per 100,000 person-years, P=.27). The most common malignancies among women were lung cancer, head and neck cancer, cervical cancer and Hodgkin's lymphoma. CONCLUSIONS: Men with HIV infection showed a statistically significant higher incidence of malignancies compared to the general Spanish population. Lung cancer was the most common non-AIDS defining cancer.

Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: Prospective, non-randomized trial.

OBJECTIVES: To assess the efficacy and safety of hydroxychloroquine (HCQ) compared with no treatment in healthcare workers with mild SARS-CoV-2 infection. METHODS: Prospective, non-randomized study. All health professionals with confirmed COVID-19 between April 7 and May 6, 2020, non-requiring initial hospitalization were asked to participate. Patients who accepted treatment were given HCQ for five days (loading dose of 400mg q12h the first day followed by200mg q12h). Control group included patients with contraindications for HCQ or who rejected treatment. Study outcomes were negative conversion and viral dynamics of SARS-CoV-2, symptoms duration and disease progression. RESULT: Overall, 142 patients were enrolled: 87 in treatment group and 55 in control group. The median age was 37 years and 75% were female, with few comorbidities. There were no significant differences in time to negative conversion of PCR between both groups. The only significant difference in the probability of negative conversion of PCR was observed at day 21 (18.7%, 95%CI 2.0-35.4). The decrease of SARS-CoV-2 viral load during follow-up was similar in both groups. A non significant reduction in duration of some symptoms in HCQ group was observed. Two patients with HCQ and 4 without treatment developed pneumonia. No patients required admission to the Intensive Care Unit or died. About 50% of patients presented mild side effects of HCQ, mainly diarrhea. CONCLUSIONS: Our study failed to show a substantial benefit of HCQ in viral dynamics and in resolution of clinical symptoms in health care workers with mild COVID-19.

Latency reversal agents affect differently the latent reservoir present in distinct CD4+ T subpopulations.

Latency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.

Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab.

The identification of exclusive markers to target HIV-reservoir cells will represent a significant advance in the search for therapies to cure HIV. Here, we identify the B lymphocyte antigen CD20 as a marker for HIV-infected cells in vitro and in vivo. The CD20 molecule is dimly expressed in a subpopulation of CD4-positive (CD4+) T lymphocytes from blood, with high levels of cell activation and heterogeneous memory phenotypes. In lymph node samples from infected patients, CD20 is present in productively HIV-infected cells, and ex vivo viral infection selectively upregulates the expression of CD20 during early infection. In samples from patients on antiretroviral therapy (ART) this subpopulation is significantly enriched in HIV transcripts, and the anti-CD20 monoclonal antibody Rituximab induces cell killing, which reduces the pool of HIV-expressing cells when combined with latency reversal agents. We provide a tool for targeting this active HIV-reservoir after viral reactivation in patients while on ART.

Effectiveness of Once/Day Dolutegravir Plus Boosted Darunavir as a Switch Strategy in Heavily Treated Patients with Human Immunodeficiency Virus.

STUDY OBJECTIVE: Dual therapy with once/day dolutegravir (DTG) plus boosted darunavir (DRV/b) may be a suitable and effective strategy with a high genetic barrier to resistance in patients infected with human immunodeficiency virus (HIV). Our aim was to evaluate the effectiveness of DTG plus DRV/b (DTG+DRV/b) as a switch strategy in HIV-infected patients, irrespective of their history of virologic failure (VF). DESIGN: Multicenter retrospective cohort study. SETTING: Human immunodeficiency outpatient treatment clinics at three university hospitals in Spain. PATIENTS: Fifty HIV-infected adults who had a stable antiretroviral treatment (ART) regimen and an undetectable viral load for at least 6 months, and whose ART was switched to once/day DTG+DRV/b between January 2015 and January 2018 were included in the analysis. Historical genotype at the time of VF was available in 44 patients. MEASUREMENTS AND MAIN RESULTS: Patients were followed until VF or treatment discontinuation for any reason. The primary outcome was the percentage of patients with a viral load of 50 copies/mL or lower at the last follow-up visit. Secondary outcomes included changes in CD4+ cell count, lipid profile, and renal function. Of the 50 patients included, median time of viral suppression was 52 months (interquartile range [IQR] 18-103 mo) and nadir CD4+ 89 cells/mm3 (IQR 37-241 cells/mm3 ). Patients had a history of a median of 8 ART combinations (IQR 4-11 combinations) and 3 VFs (IQR 2-8 VFs). The historical genotypes from 44 patients showed 41 patients (93.2%) with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance-associated mutations (RAMs), 32 (72.7%) with nonnucleoside reverse transcriptase inhibitor (NNRTI) RAMs, and 12 (27.3%) with primary protease inhibitor (PI) RAMs; 7 (15.9%) had darunavir RAMs, and no patients had baseline integrase strand transfer inhibitor RAMs. Thirty-seven patients (84.1%) had resistance to at least two antiretroviral classes. After a median of 25 months (IQR 17-28 mo) of follow-up, 49 patients (98%) maintained a viral load of 50 copies/mL or lower, and 1 patient (2%) had VF. No new RAMs emerged at VF. At week 4, serum creatinine concentration increased a median of 0.12 mg/dl (0.03-0.23 mg/dl). At last visit, total cholesterol and low-density lipoprotein cholesterol levels increased by a median of 9 mg/dl (IQR -18 to 40 mg/dl) and 16 mg/dl (IQR -9 to 40 mg/dl), respectively, whereas CD4+ cell count remained stable (median +13 cell/mm3 ). CONCLUSION: In this cohort of heavily treated HIV-infected patients with virologic suppression, switching to the combination of DTG+DRV/b was a convenient regimen that was highly effective and had good tolerability.

New Dual Combination of Dolutegravir-Rilpivirine for Switching to Maintenance Antiretroviral Therapy.

Advances in antiretroviral therapy have led to dramatic improvements in survival of HIV-infected persons. However, HIV cure remains elusive and lifelong treatment is needed. Attempts for reducing long-term drug exposure, toxicities, and cost, while maintaining viral suppression, have led to explore whether maintenance strategies with less than triple therapy could be feasible using the newest more potent antiretrovirals. While monotherapies have failed to do so with selection of drug resistance, some dual combinations have proven its efficacy when used sequentially in patients with viral suppression under standard triple regimens. Furthermore, the advent of coformulations makes easier long-term drug adherence. Herein, we review the current experience with the new single tablet regimen of dolutegravir (DTG) and rilpivirine (RPV) (Juluca®). It is the first approved two-drug single-tablet regimen and the first dual nuc-sparing coformulation. Two randomized, non-inferiority clinical trials (SWORD-1 and -2) and five observational studies have evaluated DTG-RPV in treatment-experienced patients. Despite distinct inclusion criteria, more than 95% of patients kept plasma HIV-RNA undetectable for at least 48 weeks. Along with virological efficacy being non-inferior to triple regimens, the tolerance of DTG-RPV was good, being discontinuations due to adverse events only 0.8-7.9%. Moreover, improvements were seen in lipid profiles in patients switched from protease inhibitors, and in renal and bone biomarkers in those switched from tenofovir disoproxil fumarate. Finally, resistance is rare failing on DTG-RPV. In summary, DTG-RPV is a novel two-drug coformulation that can be effectively and safely used in treatment-experienced patients with viral suppression if the virus is fully susceptible to both drugs. Its unique features make this drug one of the best options as long-term regimen or lifelong maintenance HIV therapy.

Impacto económico asociado a la implementación de las recomendaciones con grado de evidencia A-I del documento de consenso de GeSIDA/PNS (2015) relativas a la optimización del tratamiento antirretroviral en adultos infectados por virus de la inmunodeficiencia humana con carga viral suprimida en España / Economic impact of optimising antiretroviral treatment in human immunodeficiency virus-infected adults with suppressed viral load in Spain, by implementing the grade A-1 evidence recommendations of the 2015 GESIDA/National AIDS Plan

Introducción: El objetivo de este estudio es estimar el impacto económico en España de la optimización del tratamiento antirretroviral (TAR) triple en pacientes con carga viral suprimida según las recomendaciones GeSIDA/PNS (2015) y su aplicabilidad en la práctica clínica. Métodos: A partir de los datos de prescripción del TAR de la encuesta hospitalaria 2014, siguiendo las recomendaciones de GeSIDA/PNS de optimización de TAR con grado de evidencia A-I, se desarrolló un modelo farmacoeconómico. Las pautas de optimización, la voluntad de optimización y demás asunciones y resultados del modelo fueron validados por un panel de expertos en la infección por VIH (infectológos y farmacéuticos hospitalarios). El análisis se realizó desde la perspectiva del SNS, considerando el coste farmacológico anual, precio de venta del laboratorio notificado, deducción RD-Ley-8/2010 e IVA. Resultados: El panel seleccionó 6 estrategias de optimización y estimó que en España de los 80.859 pacientes actualmente en TAR triple, 10.863 (13,4%) serían candidatos a optimizar su TAR según estas estrategias, generando ahorros de 15,9M euros /año (2,4% del coste farmacológico del TAR triple). Las estrategias más factibles (>40% del total de pacientes candidatos a optimizar, n=4.556) y asociadas a mayores reducciones del gasto (ahorro entre 653 y 4.797 euros /paciente-año según el TAR triple de partida) serían las optimizaciones a ATV/r+3TC. Conclusión: La aplicación a la práctica clínica española de las principales estrategias de optimización recomendadas en el documento GeSIDA/PNS (2015) generaría ahorros sustanciales, especialmente aquellas basadas en biterapia con ATV+3TC, contribuyendo así al control del gasto farmacéutico y a la sostenibilidad del SNS (AU)

Introduction: The objective of this study is to estimate the economic impact associated with the optimisation of triple antiretroviral treatment (ART) in patients with undetectable viral load according to the recommendations from the GeSIDA/PNS (2015) Consensus and their applicability in the Spanish clinical practice. Methods: A pharmacoeconomic model was developed based on data from a National Hospital Prescription Survey on ART (2014) and the A-I evidence recommendations for the optimisation of ART from the GeSIDA/PNS (2015) consensus. The optimisation model took into account the willingness to optimise a particular regimen and other assumptions, and the results were validated by an expert panel in HIV infection (Infectious Disease Specialists and Hospital Pharmacists). The analysis was conducted from the NHS perspective, considering the annual wholesale price and accounting for deductions stated in the RD-Law 8/2010 and the VAT. Results: The expert panel selected six optimisation strategies, and estimated that 10,863 (13.4%) of the 80,859 patients in Spain currently on triple ART, would be candidates to optimise their ART, leading to savings of 15.9M euros /year (2.4% of total triple ART drug cost). The most feasible strategies (>40% of patients candidates for optimisation, n=4,556) would be optimisations to ATV/r+3TC therapy. These would produce savings between 653 euros and 4,797 euros per patient per year depending on baseline triple ART. Conclusion: Implementation of the main optimisation strategies recommended in the GeSIDA/PNS (2015) Consensus into Spanish clinical practice would lead to considerable savings, especially those based in dual therapy with ATV/r+3TC, thus contributing to the control of pharmaceutical expenditure and NHS sustainability (AU)

Antiretroviral Therapy in Advanced HIV Disease: Which is the Best Regimen?

Advanced HIV disease, defined as a CD4 cell count below 200 cells/µl or the presence of an AIDS-defining illness, remains common among HIV-infected individuals who first present for medical care. In developed countries, nearly 30% of new HIV diagnoses occurred at advanced stages of the disease, and it is important because advanced HIV disease has been associated with worse clinical outcomes, including lower rates of virological response, higher morbidity, and higher mortality. However, there are scarce data regarding which is the best antiretroviral regimen in these patients. Nowadays, integrase inhibitor-based regimens are widely recommended as the best initial therapy for treatment-naïve HIV-infected patients by all international guidelines. However, these guidelines hardly mention the recommended regimens in individuals with advanced HIV disease. Otherwise, recent data indicating a higher risk of immune reconstitution inflammatory syndrome associated to the use of integrase inhibitors have raised concerns on the use of these drugs in patients with advanced HIV disease. The aim of this article is to review the available evidence from randomized clinical trials for the best treatment in patients with advanced HIV disease.

Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients.

Objectives: To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. Methods: Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). Etravirine or darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. Darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. Results: Etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0-24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. Etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. Conclusions: Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice.

Economic impact of optimising antiretroviral treatment in human immunodeficiency virus-infected adults with suppressed viral load in Spain, by implementing the grade A-1 evidence recommendations of the 2015 GESIDA/National AIDS Plan. / Impacto económico asociado a la implementación de las recomendaciones con grado de evidencia A-I del documento de consenso de GeSIDA/PNS (2015) relativas a la optimización del tratamiento antirretroviral en adultos infectados por virus de la inmunodeficiencia humana con carga viral suprimida en España.

INTRODUCTION: The objective of this study is to estimate the economic impact associated with the optimisation of triple antiretroviral treatment (ART) in patients with undetectable viral load according to the recommendations from the GeSIDA/PNS (2015) Consensus and their applicability in the Spanish clinical practice. METHODS: A pharmacoeconomic model was developed based on data from a National Hospital Prescription Survey on ART (2014) and the A-I evidence recommendations for the optimisation of ART from the GeSIDA/PNS (2015) consensus. The optimisation model took into account the willingness to optimise a particular regimen and other assumptions, and the results were validated by an expert panel in HIV infection (Infectious Disease Specialists and Hospital Pharmacists). The analysis was conducted from the NHS perspective, considering the annual wholesale price and accounting for deductions stated in the RD-Law 8/2010 and the VAT. RESULTS: The expert panel selected six optimisation strategies, and estimated that 10,863 (13.4%) of the 80,859 patients in Spain currently on triple ART, would be candidates to optimise their ART, leading to savings of €15.9M/year (2.4% of total triple ART drug cost). The most feasible strategies (>40% of patients candidates for optimisation, n=4,556) would be optimisations to ATV/r+3TC therapy. These would produce savings between €653 and €4,797 per patient per year depending on baseline triple ART. CONCLUSION: Implementation of the main optimisation strategies recommended in the GeSIDA/PNS (2015) Consensus into Spanish clinical practice would lead to considerable savings, especially those based in dual therapy with ATV/r+3TC, thus contributing to the control of pharmaceutical expenditure and NHS sustainability.

Dual Therapy With Darunavir and Ritonavir Plus Lamivudine vs Triple Therapy With Darunavir and Ritonavir Plus Tenofovir Disoproxil Fumarate and Emtricitabine or Abacavir and Lamivudine for Maintenance of Human Immunodeficiency Virus Type 1 Viral Suppression: Randomized, Open-Label, Noninferiority DUAL-GESIDA 8014-RIS-EST45 Trial.

BACKGROUND: Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression. METHODS: This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm. RESULTS: A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual- and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference, -3.8%; 95% confidence interval, -11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively. CONCLUSIONS: Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy. CLINICAL TRIALS REGISTRATION: NCT02159599.

A Novel Single-Cell FISH-Flow Assay Identifies Effector Memory CD4+ T cells as a Major Niche for HIV-1 Transcription in HIV-Infected Patients.

Cells that actively transcribe HIV-1 have been defined as the "active viral reservoir" in HIV-infected individuals. However, important technical limitations have precluded the characterization of this specific viral reservoir during both treated and untreated HIV-1 infections. Here, we used a novel single-cell RNA fluorescence in situ hybridization-flow cytometry (FISH-flow) assay that requires only 15 million unfractionated peripheral blood mononuclear cells (PBMCs) to characterize the specific cell subpopulations that transcribe HIV RNA in different subsets of CD4+ T cells. In samples from treated and untreated HIV-infected patients, effector memory CD4+ T cells were the main cell population supporting HIV RNA transcription. The number of cells expressing HIV correlated with the plasma viral load, intracellular HIV RNA, and proviral DNA quantified by conventional methods and inversely correlated with the CD4+ T cell count and the CD4/CD8 ratio. We also found that after ex vivo infection of unstimulated PBMCs, HIV-infected T cells upregulated the expression of CD32. In addition, this new methodology detected increased numbers of primary cells expressing viral transcripts and proteins after ex vivo viral reactivation with latency reversal agents. This RNA FISH-flow technique allows the identification of the specific cell subpopulations that support viral transcription in HIV-1-infected individuals and has the potential to provide important information on the mechanisms of viral pathogenesis, HIV persistence, and viral reactivation.IMPORTANCE Persons infected with HIV-1 contain several cellular viral reservoirs that preclude the complete eradication of the viral infection. Using a novel methodology, we identified effector memory CD4+ T cells, immune cells preferentially located in inflamed tissues with potent activity against pathogens, as the main cells encompassing the transcriptionally active HIV-1 reservoir in patients on antiretroviral therapy. Importantly, the identification of such cells provides us with an important target for new therapies designed to target the hidden virus and thus to eliminate the virus from the human body. In addition, because of its ability to identify cells forming part of the viral reservoir, the assay used in this study represents an important new tool in the field of HIV pathogenesis and viral persistence.