HTLV-2 Enhances CD8+ T Cell-Mediated HIV-1 Inhibition and Reduces HIV-1 Integrated Proviral Load in People Living with HIV-1.

People living with HIV-1 and HTLV-2 concomitantly show slower CD4+ T cell depletion and AIDS progression, more frequency of the natural control of HIV-1, and lower mortality rates. A similar beneficial effect of this infection has been reported on HCV coinfection reducing transaminases, increasing the spontaneous clearance of HCV infection and delaying the development of hepatic fibrosis. Given the critical role of CD8+ T cells in controlling HIV-1 infection, we analysed the role of CD8+ T cell-mediated cytotoxic activity in coinfected individuals living with HIV-1. One hundred and twenty-eight individuals living with HIV-1 in four groups were studied: two groups with HTLV-2 infection, including individuals with HCV infection (N = 41) and with a sustained virological response (SVR) after HCV treatment (N = 25); and two groups without HTLV-2 infection, including individuals with HCV infection (N = 25) and with a sustained virological response after treatment (N = 37). We found that CD8+ T cell-mediated HIV-1 inhibition in vitro was higher in individuals with HTLV-2. This inhibition activity was associated with a higher frequency of effector memory CD8+ T cells, higher levels of granzyme A and granzyme B cytolytic enzymes, and perforin. Hence, cellular and soluble cytolytic factors may contribute to the lower HIV-1 pre-ART viral load and the HIV-1 proviral load during ART therapy associated with HTLV-2 infection. Herein, we confirmed and expanded previous findings on the role of HTLV-2 in the beneficial effect on the pathogenesis of HIV-1 in coinfected individuals.

Low risk of bacterial co-infection, opportunistic diseases, and persistent immunosuppression in people living with HIV and COVID-19.

PURPOSE: SARS-CoV-2 infection produces lymphopenia and CD4+ T-cell decrease, which could lead to a higher risk of bacterial co-infection or impair immunological evolution in people living with HIV (PLWH). METHODS: We investigated the rate of co-infection and superinfection, and the evolution of CD4+ count and CD4+/CD8+ ratio, in hospitalized PLWH with COVID-19. RESULTS: From March to December 2020, 176 PLWH had symptomatic COVID-19 and 62 required hospitalization (median age, 56 years, 89% males). At admission, 7% and 13% of patients had leukocytosis or increased procalcitonin values and 37 (60%) received empiric antibiotic therapy, but no bacterial co-infection was diagnosed. There were seven cases of superinfection (12%), and one case of P. jiroveci pneumonia during ICU stay. No significant change in CD4+ count or CD4+/CD8+ ratio was observed after discharge. CONCLUSION: Bacterial co-infection is not frequent in PLWH with COVID-19. Immune recovery is observed in most of patients after the disease.

Implementation of a lung cancer screening initiative in HIV-infected subjects.

In this pilot program of low-dose computed tomography (LDCT) for the screening of lung cancer (LC) in a targeted population of people with HIV (PWH), its prevalence was 3.6%; the number needed to screen in order to detect one case of lung cancer was 28, clearly outweighing the risks associated with lung cancer screening. While data from additional cohorts with longitudinal measurements are needed, PWH are a target population for lung cancer screening with LDCT.

Prevalence and factors associated with SARS-CoV-2 seropositivity in the Spanish HIV Research Network Cohort.

OBJECTIVES: We aimed to assess the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and factors associated with seropositivity and asymptomatic coronavirus disease 2019 (COVID-19) among people with HIV (PWH). METHODS: This was a cross-sectional study carried out within the cohort of the Spanish HIV Research Network. Participants were consecutive PWH with plasma collected from 1st April to 30th September 2020. We determined SARS-CoV-2 antibodies (Abs) in plasma. Illness severity (NIH criteria) was assessed by a review of medical records and, if needed, participant interviews. Multivariable logistic regression analysis was used to identify predictors of seropositivity among the following variables: sex, age, country of birth, education level, comorbidities (hypertension, chronic heart disease, diabetes mellitus, non-AIDS-related cancer, chronic kidney disease, cirrhosis), route of HIV acquisition, prior AIDS, CD4+ cell count, HIV viral load, nucleoside/nucleotide reverse transcriptase inhibitor (N [t]RTI) backbone, type of third antiretroviral drug, and month of sample collection. RESULTS: Of 1076 PWH (88.0% males, median age 43 years, 97.7% on antiretroviral therapy, median CD4+ 688 cells/mm3, 91.4% undetectable HIV viral load), SARS-CoV-2 Abs were detected in 91 PWH, a seroprevalence of 8.5% (95%CI 6.9-10.3%). Forty-five infections (45.0%) were asymptomatic. Variables independently associated with SARS-CoV-2 seropositivity were birth in Latin American countries versus Spain (adjusted odds ratio (aOR) 2.30, 95%CI 1.41-3.76, p 0.001), and therapy with tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) versus tenofovir alafenamide (TAF)/FTC as the N(t)RTI backbone (aOR 0.49, 95%CI 0.26-0.94, p 0.031). CONCLUSIONS: Many SARS-CoV-2 infections among PWH were asymptomatic, and birth in Latin American countries increased the risk of SARS-CoV-2 seropositivity. Our analysis, adjusted by comorbidities and other variables, suggests that TDF/FTC may prevent SARS-CoV-2 infection among PWH.

Description of COVID-19 in HIV-infected individuals: a single-centre, prospective cohort.

BACKGROUND: Information about incidence, clinical characteristics, and outcomes of HIV-infected individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is scarce. We characterised individuals with COVID-19 among a cohort of HIV-infected adults in Madrid. METHODS: In this observational prospective study, we included all consecutive HIV-infected individuals (aged ≥18 years) who had suspected or confirmed COVID-19 as of April 30, 2020, at the Hospital Universitario Ramón y Cajal (Madrid, Spain). We compared the characteristics of HIV-infected individuals with COVID-19 with a sample of HIV-infected individuals assessed before the COVID-19 pandemic, and described the outcomes of individuals with COVID-19. FINDINGS: 51 HIV-infected individuals were diagnosed with COVID-19 (incidence 1·8%, 95% CI 1·3-2·3). Mean age of patients was 53·3 years (SD 9·5); eight (16%) were women, and 43 (84%) men. 35 (69%) cases of co-infection had laboratory confirmed COVID-19, and 28 (55%) required hospital admission. Age and CD4 cell counts in 51 patients diagnosed with COVID-19 were similar to those in 1288 HIV-infected individuals without; however, 32 (63%) with COVID-19 had at least one comorbidity (mostly hypertension and diabetes) compared with 495 (38%) without COVID-19 (p=0·00059). 37 (73%) patients had received tenofovir before COVID-19 diagnosis compared with 487 (38%) of those without COVID-19 (p=0·0036); 11 (22%) in the COVID-19 group had previous protease inhibitor use (mostly darunavir) compared with 175 (14%; p=0·578). Clinical, analytical, and radiological presentation of COVID-19 in HIV-infected individuals was similar to that described in the general population. Six (12%) individuals were critically ill, two of whom had CD4 counts of less than 200 cells per µL, and two (4%) died. SARS-CoV-2 RT-PCR remained positive after a median of 40 days from symptoms onset in six (32%) individuals, four of whom had severe disease or low nadir CD4 cell counts. INTERPRETATION: HIV-infected individuals should not be considered to be protected from SARS-CoV-2 infection or to have lower risk of severe disease. Generally, they should receive the same treatment approach applied to the general population. FUNDING: None.

Increased HIV infection in patients with stroke in Spain. A 16-year population-based study / Aumento de la infección por VIH en pacientes con ictus en España. Estudio poblacional a nivel nacional a lo largo de 16 años

INTRODUCTION: An increased incidence of stroke in HIV-infected patients has already been reported, suggesting that HIV infection may be a cerebrovascular risk factor. The objective of this study was to assess temporal trends in the proportion of HIV infection among patients with stroke in Spain. METHODS: Data were obtained from the minimum basic dataset (MBDS) of all patients hospitalized in Spain between 1997 and 2012 with a primary or secondary diagnosis of stroke. The annual proportion of HIV infection and time trends (stratifying by type of stroke and HIV stage) were calculated, and predictors of HIV infection and the social and economic impact of HIV-infected (HIV+) and non-infected (HIV−) patients were analyzed. RESULTS: Of 857,371 patients hospitalized with an incident stroke, 2134 (0.25%) had HIV infection. A 2.5% year-on-year increase (OR 1.025, 95% CI 1.015-1.036, p < 0.0001) of the proportion of HIV-infected patients was observed due to an increase in the asymptomatic stage of the infection (per year OR 1.077, 95% CI 1.057-1.097, p < 0.0001), as the proportion of patients with AIDS remained stable. Factors independently associated with HIV infection and stroke were active smoking, stimulating drugs and hepatitis C virus (HCV) infection. A higher mortality rate, longer hospital stay and a higher cost per hospitalized patient was observed among HIV+ patients. CONCLUSIONS: From 1997 to 2012, there was an increase in the proportion of HIV infection among patients hospitalized with stroke irrespective of the classical vascular risk factors, reinforcing the role of HIV infection as a cerebrovascular risk factor

INTRODUCCIÓN: Se ha observado previamente un aumento de la incidencia de ictus en pacientes con VIH (VIH+), lo que sugiere que esta infección es un factor de riesgo cerebrovascular (FRCV). El objetivo fue analizar las tendencias temporales del porcentaje de VIH+ en pacientes con ictus en España. MÉTODOS: Los datos se obtuvieron del Conjunto Mínimo Básico de Datos (CMBD), incluyendo a todos los pacientes hospitalizados en España entre 1997 y 2012 con un diagnóstico primario o secundario de ictus. Se calcularon el porcentaje anual de infección por VIH y las tendencias temporales (estratificados por el tipo de ictus y el estadio del VIH), así como los factores predictores independientes de infección por VIH en pacientes con ictus. La mortalidad, las estancias hospitalarias y el coste por paciente fueron similares entre los pacientes VIH+ y los pacientes no infectados por el VIH (VIH-). RESULTADOS: De los 857.371 pacientes hospitalizados con un ictus incidente, 2.134 (0,25%) presentaban infección por VIH. Se observó un aumento de un 2,5% anual (OR: 1,025; IC del 95%: 1,015-1,036; p < 0,0001) en el porcentaje de infección por VIH, secundario a un aumento en el estadio asintomático de la infección (OR anual: 1,077; IC del 95%: 1,057-1,097; p < 0,0001), puesto que el porcentaje permaneció estable en pacientes con SIDA. La infección por el virus de la hepatitis C (VHC), el consumo de drogas estimulantes y el tabaquismo activo fueron factores independientemente asociados a sufrir un ictus y presentar VIH. Se observó una mayor mortalidad (OR: 1,81; p < 0,0001) y una mayor estancia hospitalaria y coste por paciente hospitalizado en los pacientes VIH+. CONCLUSIONES: De 1997 a 2012, se ha observado un aumento del porcentaje de infección por VIH en pacientes hospitalizados con ictus independientemente de los factores de riesgo clásicos, lo que refuerza el papel de las infecciones por VIH como FRCV

CD4+:CD8+ T-cell ratio changes in people with HIV receiving antiretroviral treatment.

BACKGROUND: Cofactors associated with persistently abnormal CD4+:CD8+ T-cell ratio in people with HIV (PWH) on antiretroviral treatment (ART) might change over time as the population of people with HIV ages or as new ART drugs become available. The main objective of our study was to determine the long-term associations of baseline factors, including the CD4+ T-cell count and ratio, with ratio normalization (≥1). In addition to this, we explored whether the ratio remained associated with the risk of both AIDS and non-AIDS events among individuals on suppressive ART. METHODS: Clinic-based study in a tertiary, university hospital in Madrid. People with HIV starting a first-line ART regimen (January 2006-June 2017) were included in a prospective national multicentre cohort (CoRIS). People with controlled HIV-infection within the first year of ART initiation and complete CD4+ and CD8+ T-cell records were selected. Cox proportional hazard (PH) regression models were used to estimate the cumulative incidence of ratio normalization and to examine associations with socio-demographic and clinical variables. To investigate factors independently associated with the development of AIDS and non-AIDS events we used a time updated Poisson regression model. RESULTS: The study included 557 subjects. During follow-up (median 5.24 years), 44% of participants achieved a ratio of 1 within a median of 1.49 years. In a multivariate PH model, pre-ART factors negatively associated with ratio normalization were the pre-ART CD4+:CD8+ T-cell ratio and mode of HIV acquisition. For the secondary analysis, 1.3 events/100 person years of follow-up were observed. After adjustment, older age, HIV RNA >200 copies/ml and CD4+:CD8+ T-cell ratios over follow-up, remained significantly associated with the development of AIDS and non-AIDS events. In contrast, pre-ART ratio was not associated with the risk of AIDS and non-AIDS events. CONCLUSIONS: In summary, our study showed that higher pre-ART CD4+:CD8+ T-cell ratio is associated with rates of ratio normalization ≥1. In addition, the risk of AIDS and non-AIDS events seems to be predicted by the time updated CD4+:CD8+ T-cell ratio not by the pre-ART CD4+:CD8+ T-cell ratio. Therefore, CD4+:CD8+ T-cell ratio should be considered as a dynamic marker for translation into clinical practice.

Risk, Diagnostic and Predictor Factors for Classical Hodgkin Lymphoma in HIV-1-Infected Individuals: Role of Plasma Exosome-Derived miR-20a and miR-21.

The incidence of classical Hodgkin lymphoma (cHL) in the HIV-1 setting has increased 5-25-fold compared to that observed in the general population. This study aimed to determine whether selected micro RNAs (miRs) and other soluble biomarkers and cellular subsets are dysregulated in cHL and could be used as biomarkers. This was a retrospective and longitudinal matched case-control study of 111 Caucasian, HIV-1-infected adult individuals, including 37 individuals with cHL and 74 with no type of cancer. Immunovirological data, plasma exosome-derived miR-16, miR-20a, miR-21, miR-221, miR-223, miR-106a, miR-185, miR-23, miR-30d, miR-222, miR-146a and miR-324, plasma IL-6, sCD14, sCD27, sCD30, sIL-2R, TNFR1, and cell phenotyping of T and B lymphocytes and natural killer (NK) cells were analyzed. Before cHL diagnosis, miR-20a, miR-21, and sCD30 were higher in cHL (p = 0.008, p = 0.009 and p = 0.042, respectively), while miR-16 was down-regulated (p = 0.040). miR-20a and miR-21 were independently associated with cHL (p = 0.049 and p = 0.035, respectively). The combination of miR-20a and miR-21 showed a good AUC value of 0.832 with a moderate likelihood ratio positive (LR+) value of 5.6 and a slight likelihood ratio negative (LR-) value of 0.23. At cHL diagnosis, miR-20a, miR-21 and miR-324 were overexpressed in cHL (p = 0.005, p = 0.024, and p = 0.001, respectively), while miR-223, miR-16, miR-185 and miR-106a were down regulated (p = 0.042, p = 0.007, p = 0.006, and p = 0.002, respectively). In addition, sCD14, sCD27, sCD30 and IL2R levels were higher in these individuals (p = 0.038, p = 0.010, p = 0.030, p = 0.006, respectively). miR-20a was independently associated with cHL (p = 0.011). The diagnostic value of miR-20a showed good AUC value of 0.754 (p = 0.074) with a slight LR+ value of 2 and a slight LR- of 0.25. After chemotherapy, miR-20a was higher in those individuals who had an adverse outcome (p < 0.001), while sCD14 and sCD30 were higher (p < 0.001). A specific signature of miRs and cytokines associated with a subsequent cHL diagnosis was found in this study, especially miR-20a and miR-21. Also, another biomarker signature was found at cHL diagnosis, with a relevant discriminant disease value for miR-20a. Of note, miR-20a expression was higher in those individuals who had an adverse clinical outcome after chemotherapy.

Weight gain in people living with HIV switched to dual therapy: changes in body fat mass.

: Changes in weight and body composition were assessed in long-term suppressed HIV-infected patients switching to dolutegravir/rilpivirine (n = 37), and compared with similar patients switching to darunavir/lamivudine (n = 17). At month 12, weight significantly increased with dolutegravir/rilpivirine (1.8 kg, IQR -1.2 to 4.1; 2.5%; P = 0.03). A follow-up DXA (median, 16 months) showed similar increases in trunk (7.8%), arms (5.6%), and legs (6.2%) fat mass, without changes in lean mass. Despite lower weight gain (0.70 kg, IQR -0.8 to 4.0, P = 0.28), fat mass increase was similar in the darunavir/lamivudine group. Baseline fat mass and CD4 counts were the only factors explaining fat mass gain.

Factors associated with the number of drugs in darunavir/cobicistat regimens.

BACKGROUND: Darunavir/cobicistat can be used as mono, dual, triple or more than triple therapy. OBJECTIVES: To assess factors associated with the number of drugs in darunavir/cobicistat regimens. METHODS: A nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat in Spain from July 2015 to May 2017. Baseline characteristics, efficacy and safety at 48 weeks were compared according to the number of drugs used. RESULTS: There were 761 patients (75% men, 98% were antiretroviral-experienced, 32% had prior AIDS, 84% had HIV RNA <50 copies/mL and 88% had ≥200 CD4 cells/mm3) who initiated darunavir/cobicistat as mono (n=308, 40%), dual (n=173, 23%), triple (n=253, 33%) or four-drug (n=27, 4%) therapy. Relative to monotherapy, triple therapy was more common in men aged <50 years, with prior AIDS and darunavir plus ritonavir use, and with CD4 cells <200/mm3 and with detectable viral load at initiation of darunavir/cobicistat; dual therapy was more common with previous intravenous drug use, detectable viral load at initiation of darunavir/cobicistat and no prior darunavir plus ritonavir; and four-drug therapy was more common with prior AIDS and detectable viral load at initiation of darunavir/cobicistat. Monotherapy and dual therapy showed a trend to better virological responses than triple therapy. CD4 responses and adverse effects did not differ among regimens. DISCUSSION: Darunavir/cobicistat use in Spain has been tailored according to clinical characteristics of HIV-infected patients. Monotherapy and dual therapy have been common and preferentially addressed to older patients with a better HIV status, suggesting that health issues other than HIV infection may have been strong determinants of its prescription.

Increased HIV infection in patients with stroke in Spain. A 16-year population-based study.

INTRODUCTION: An increased incidence of stroke in HIV-infected patients has already been reported, suggesting that HIV infection may be a cerebrovascular risk factor. The objective of this study was to assess temporal trends in the proportion of HIV infection among patients with stroke in Spain. METHODS: Data were obtained from the minimum basic dataset (MBDS) of all patients hospitalized in Spain between 1997 and 2012 with a primary or secondary diagnosis of stroke. The annual proportion of HIV infection and time trends (stratifying by type of stroke and HIV stage) were calculated, and predictors of HIV infection and the social and economic impact of HIV-infected (HIV+) and non-infected (HIV-) patients were analyzed. RESULTS: Of 857,371 patients hospitalized with an incident stroke, 2134 (0.25%) had HIV infection. A 2.5% year-on-year increase (OR 1.025, 95% CI 1.015-1.036, p<0.0001) of the proportion of HIV-infected patients was observed due to an increase in the asymptomatic stage of the infection (per year OR 1.077, 95% CI 1.057-1.097, p<0.0001), as the proportion of patients with AIDS remained stable. Factors independently associated with HIV infection and stroke were active smoking, stimulating drugs and hepatitis C virus (HCV) infection. A higher mortality rate, longer hospital stay and a higher cost per hospitalized patient was observed among HIV+ patients. CONCLUSIONS: From 1997 to 2012, there was an increase in the proportion of HIV infection among patients hospitalized with stroke irrespective of the classical vascular risk factors, reinforcing the role of HIV infection as a cerebrovascular risk factor.

High CD8 T cell percentage and HCV replication control are common features in HIV-1 controllers and HTLV-2-co-infected patients with a history of injection drug use.

HTLV-2/HIV-1-coinfected patients and HIV-infected patients with natural HIV-1 control show an immune capacity that allows some control of viral infections. These two groups of patients have showed an immune capacity that allows them to have some control over viral infections, very strong control of HIV-1 replication in the case of HIV-1 controllers. The purpose of this retrospective cross-sectional study was to compare viral and immunologic parameters between three cohorts of Caucasian adult HIV-1-infected patients, including HIV-1 controllers (29 patients), HTLV-2/HIV-1 chronic progressors (56 patients), and HIV-1 chronic progressors (101 patients), followed in two different tertiary University Hospitals in Spain. Demographic parameters, nadir CD4 T cell count, CD4 and CD8 T cell counts and percentage, anti-HCV antibodies, HCV RNA load, HCV genotype, HIV-1 RNA loads, and anti-HTLV-2 antibodies were analyzed. HIV-1 controllers and HTLV-2/HIV-1 chronic progressors were younger and with shorter time since HIV-1 diagnosis compared to HIV-1 chronic progressors. HIV-1 controllers and HTLV-2/HIV-1 chronic progressors had significantly higher CD8 T cell percentage (p = 0.002 and p = 0.016, respectively) and lower levels of HCV RNA loads (0.015 and 0.007, respectively) compared to that of HIV-1 chronic progressors. Multivariate analyses showed that gender and HTLV-2 infection were independently associated to HCV RNA load, while only HTLV-2 infection was independently associated to CD8 T cell percentage. The implication of HTLV-2 infection in the control of HIV-1 and HCV infections is worth being further analyze.

Frailty phenotype: a clinical marker of age acceleration in the older HIV-infected population.

AIM: To evaluate the association between DNA methylation and frailty in the HIV-infected population and to investigate the usefulness of assessing frailty as a clinical marker to identify age acceleration. METHODS: Frailty was assessed according to Fried's frailty phenotype. DNA methylation was analyzed in 10 frail patients, and compared with 10 robust control patients, all with HIV. Predicted age was inferred using the Weidner's formula. Age acceleration was assessed using the difference between predicted and chronological age. RESULTS: HIV-infected frail patients had significantly higher biological predicted ages than chronological ages (mean acceleration: 10.3 years; p = 0.012). CONCLUSIONS: We link age acceleration and frailty in an older HIV population. Frailty could be used in this population for implementing specific clinical approaches.

Frailty and physical function in older HIV-infected adults.

Background and Objectives: HIV patients have seen accelerated ageing. Our objective was to determine the prevalence of frailty, to evaluate factors associated with frailty and to evaluate physical function in older HIV-infected adults. Design: this was a cross-sectional study. Setting: outpatient clinics of two public university hospitals in Madrid (Spain). Methods: frailty was defined according to the criteria of Fried: shrinking, weakness, poor endurance and energy, slowness and low physical activity level, being frail those who met at least three criteria, prefrail one or two criteria and robust when they met no criteria. Physical function was assessed using standardised methods. Results: we evaluated 117 HIV-infected patients. Mean age was 61.3 ([standard deviation] 6.87) years. All patients were on antiretroviral therapy. Median current CD4+ T-cell count was 638 (144-1871) cells/µl, and median CD4/CD8 ratio was 0.79 (0.00-3.62). The prevalence of frailty was 15.4%, and that of prefrailty was 52.1%. In the multivariate analyses depressive symptoms (OR [95% CI], 9.20 [2.17-39.05]) and CD4/CD8 ratio (OR 0.11 [0.02-0.61]) were associated with frailty. Even though 100% of the patients were able to walk and perform basic activities of daily life independently, functional impairment was high (20% slow gait and 55% Short Physical Performance Battery ≤9). Conclusions: HIV-infected patients aged ≥55 years have a high prevalence of frailty and a high burden of functional impairment. Optimal management of this population requires close collaboration between infectious diseases specialists and geriatricians.

Changes in Kidney Function and in the Rate of Tubular Dysfunction After Tenofovir Withdrawal or Continuation in HIV-Infected Patients.

INTRODUCTION: Longitudinal data on the changes in kidney function and tubular abnormalities in case of tenofovir disoproxil fumarate (TDF) withdrawal or continuation are scarce. METHODS: Prospective study of 228 patients receiving TDF, with 3 sequential determinations of serum creatinine, estimated glomerular filtration rate (eGFR), phosphatemia, and different urinary parameters (protein, albumin, phosphaturia, uricosuria, and glycosuria). Changes were analyzed in patients who interrupted TDF as compared to those who continued the same regimen. Proximal renal tubular dysfunction (PRTD) was defined as ≥2 tubular abnormalities. RESULTS: After a median follow-up of 59.5 months, 78 patients (34%) had PRTD, mainly proteinuria (40%) and phosphaturia (61%), and time on TDF explains the severity of tubular alterations and eGFR slopes. In 35 switching patients, there was a rapid and significant eGFR improvement (median +4.1 ml/min per 1.73 m; P = 0.02), leading to a 39%-83% reduction in the prevalence of tubular abnormalities and of PRTD in less than 1 year (66%-39%). In comparison, 193 patients continuing the same regimen for 21.2 months had a small but significant and progressive eGFR decrease (-2.9 mL·min·1.73 m; P < 0.01), and a progressive rise in the prevalence of phosphaturia, uricosuria, and glycosuria (+9%-56%). In linear mixed-effect model, subsequent eGFR impairment was associated with proteinuria and time on TDF, and eGFR improvement with TDF discontinuation. CONCLUSIONS: Our data support the role of use and time on TDF in eGFR decline and tubular dysfunction. In contrast, TDF withdrawal is followed by a rapid and significant, although partial, recovery of eGFR and tubular abnormalities.

Bone mineral density decline according to renal tubular dysfunction and phosphaturia in tenofovir-exposed HIV-infected patients.

INTRODUCTION: The mechanisms underlying the effect of tenofovir disoproxil fumarate (TDF) on the decline of bone mineral density (BMD) have not been established, especially the effect of renal tubular dysfunction. METHODS: Longitudinal study of 90 patients with two successive dual X-ray absorptiometry scans after evaluation of serum and urinary parameters (proteinuria, albuminuria, phosphaturia, uricosuria, glycosuria, ß-2-microglobulin, and retinol-binding protein). RESULTS: After a median of 38 months on TDF, osteopenia at spine and hip was observed in 49 and 48%, and osteoporosis in 9 and 2%, respectively. There was a lineal correlation between BMD at femoral neck and time on TDF (Spearman's rho = -0.27; P = 0.01). One or more tubular abnormalities were observed in 80% of cases (hyperphosphaturia, 50%). A lower BMD correlated with phosphaturia (r = -0.25; P = 0.03), even with phosphataemia within normal limits. In fact, patients with previous improvement in phosphaturia had better BMD at inclusion (Spearman's rho = -0.33; P < 0.01). A second dual X-ray absorptiometry, after a median of 40.8 months (33.8-45.1; 627.7 patients-year on TDF), showed additional BMD reduction at hip in 50% of cases (36% with bone loss >3%), a decline associated with phosphaturia (ß, -0.31; P = 0.01) or number of tubular abnormalities (ß, -0.41; P = 0.01), but also with use of boosted protease inhibitors (ß, -0.47; P = 0.03) and BMD at inclusion (ß, -0.33; P = 0.03). CONCLUSION: Chronic abnormal phosphaturia explains, at least in part, progressive bone loss during TDF therapy. These data suggest that tubular dysfunction leads to an altered equilibrium between phosphataemia, phosphaturia, and bone as mechanism of progressive BMD decline.

Bryostatin-1 for latent virus reactivation in HIV-infected patients on antiretroviral therapy.

OBJECTIVE: The protein kinase C (PKC) agonist bryostatin-1 has shown significant ex-vivo potency to revert HIV-1 latency, compared with other latency reversing agents (LRA). The safety of this candidate LRA remains to be proven in treated HIV-1-infected patients. METHODS: In this pilot, double-blind phase I clinical-trial (NCT 02269605), we included aviraemic HIV-1-infected patients on triple antiretroviral therapy to evaluate the effects of two different single doses of bryostatin-1 (10 or 20 µg/m) compared with placebo. RESULTS: Twelve patients were included, four in each arm. Bryostatin-1 was well tolerated in all participants. Two patients in the 20 µg/m arm developed grade 1 headache and myalgia. No detectable increases of cell-associated unspliced (CA-US) HIV-1-RNA were observed in any study arm, nor differences in HIV-1 mRNA dynamics between arms (P = 0.44). The frequency of samples with low-level viraemia did not differ between arms and low-level viraemia did not correlate with CA-US HIV-1-RNA levels (P = 0.676). No changes were detected on protein kinase C (PKC) activity and in biomarkers of inflammation (sCD14 and interleukin-6) in any study arm. After the single dose of bryostatin-1, plasma concentrations were under detection limits in all the patients in the 10 µg/m arm, and below 50 pg/ml (0.05 nmol/l) in those in the 20 µg/m arm. CONCLUSION: Bryostatin-1 was safe at the single doses administered. However, the drug did not show any effect on PKC activity or on the transcription of latent HIV, probably due to low plasma concentrations. This study will inform next trials aimed at assessing higher doses, multiple dosing schedules or combination studies with synergistic drugs.

Fibrosis Regression Explains Differences in Outcome in HIV-/HCV-Coinfected Patients with Cirrhosis After Sustained Virological Response.

BACKGROUND AND AIMS: Fibrosis regression (FR) after sustained virological response (SVR) should produce a better outcome in hepatitis C (HCV)-/HIV-coinfected patients with liver cirrhosis, but there are no specific data in this issue. METHODS: We compared the incidence rate (IR) and the time to develop a liver complication and death in 133 cirrhotic patients according to SVR or/and FR. RESULTS: Of 42 patients with SVR, 23 (55%) had FR, in comparison with only 14 of the 91 (15%) without SVR. During a follow-up of 6.8 years (916.8 person-years), the IR of death, liver-related death, and liver-related complications were 2.45, 0.61, and 1.22 per 100 persons/year among SVR/FR, and 7.6, 5.9, and 6.81 among non-SVR without FR (p < 0.01), respectively. SVR patients without FR had also a lower rate of liver-related complications (1.78 vs 3.25; p = 0.02), but a worse IR of death (5.36) and liver-related death (2.68) than non-SVR patients with FR (1.3, and 0.65; p < 0.01). Moreover, FR was associated with less hospital admissions and decreasing alpha-fetoprotein levels. In Cox analysis, only FR was associated with a lower risk of death (adjusted hazard ratio, HR 0.36; 95% CI 0.15-0.86), and liver-related death (HR 0.15; 95% CI 0.03-0.65), whereas both FR (HR 0.09; 95% CI 0.03-0.3, p < 0.01) and SVR (HR 0.24; 95% CI 0.07-0.87) decreased the risk of liver-related complications. CONCLUSION: Fibrosis regression after SVR is associated with the highest reduction in death of any cause, liver-related mortality, and liver-related complications in HIV-/HCV-coinfected patients with cirrhosis.

Effect of a monthly dose of calcidiol in improving vitamin D deficiency and secondary hyperparathyroidism in HIV-infected patients.

There are no data about the optimal supplementation therapy in HIV-infected patients with vitamin D (25OHD) deficiency. The aim of this study was to assess the effect of an oral monthly dose of 16,000 IU calcidiol. We performed a longitudinal cohort study of 365 HIV-infected patients (24 % females) was with sequential determinations of 25OHD, serum parathyroid hormone (PTH), calcium, and alkaline phosphatase. The efficacy and safety of supplementation in 123 patients were compared against dietary and sun exposure advice. Overall, mean baseline 25OHD levels were 19.1 ng/ml (IQR 12-23.6), 63 % of patients had 25OHD deficiency and 27 % secondary hyperparathyroidism. After a median time of 9.3 months (95.61 patients-year on-treatment), 25OHD levels increased in comparison with non-supplemented patients (+16.4 vs. +3.2 ng/ml; p < 0.01), decreasing the rate of 25OHD deficiency (from 84 to 24 %), and decreasing serum PTH (-4.9 pg/ml) and the rate of secondary hyperparathyroidism (from 43 to 31 %; p < 0.001). This improvement was observed irrespective of HIV/HCV coinfection or the use of efavirenz. In a regression analysis, adjusting by seasonality, a lower baseline 25OHD was associated with persistence of deficiency (relative risk, RR 1.07; 95 % CI 1.03-1.1; p < 0.001), whereas calcidiol supplementation was the only factor associated with significant improvement (RR 0.38; 95 % CI 0.12-0.46; p < 0.001). This monthly dose showed no clinical toxicity, and no patient had 25OHD levels above 100 ng/ml, nor hypercalcemia. The use of monthly calcidiol is safe, easy to take, and largely effective to improve vitamin D deficiency and secondary hyperparathyroidism in HIV-infected patients.