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The optimal therapeutic approach for primary HIV infection (PHI) is still debated. We aimed to compare the viroimmunological response to a four- versus a three-drug regimen, both INSTI-based, in patients with PHI. This was a monocentric, prospective, observational study including all patients diagnosed with PHI from December 2014 to April 2018. Antiretroviral therapy (ART) was started, before genotype resistance test results, with tenofovir/emtricitabine and either raltegravir plus boosted darunavir or dolutegravir. Cumulative probability of virological suppression [VS] (HIV-1 RNA< 40 cp/mL), low-level HIV-1 DNA [LL-HIVDNA] (HIV-1 DNA < 200 copies/106PBMC), and CD4/CD8 ratio ≥1 were estimated using Kaplan−Meier curves. Factors associated with the achievement of VS, LL-HIVDNA, and CD4/CD8 ≥ 1 were assessed by a Cox regression model. We enrolled 144 patients (95.8% male, median age 34 years): 110 (76%) started a four-drug-based therapy, and 34 (24%) a three-drug regimen. Both treatment groups showed a comparable high probability of achieving VS and a similar probability of reaching LL-HIVDNA and a CD4/CD8 ratio ≥1 after 48 weeks from ART initiation. Higher baseline HIV-1 RNA and HIV-1 DNA levels lowered the chance of VS, whereas a better preserved immunocompetence increased that chance. Not statistically significant factors associated with LL-HIVDNA achievement were found, whereas a higher baseline CD4/CD8 ratio predicted the achievement of immune recovery. In PHI patients, the rapid initiation of either an intensified four-drug or a standard three-drug INSTI-based regimen showed comparable responses in terms of VS, viral reservoir size, and immunological recovery.
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BACKGROUND: Sofosbuvir plus daclatasvir achieves high rates of sustained virologic response (SVR), with no differences according to HIV serostatus. However, only limited information is available on the pharmacokinetic variability of sofosbuvir and daclatasvir in HIV/HCV-coinfected patients. OBJECTIVES: The aim of this study was to identify patient-, treatment-, and disease-related factors that are significantly associated with sofosbuvir and daclatasvir plasma trough concentrations (Ctrough), including liver and renal function, among HIV/HCV-coinfected persons. METHODS: In this observational cohort pilot study, HIV/HCV-coinfected patients undergoing sofosbuvir plus daclatasvir treatment were prospectively enrolled. Biochemical and viro-immunological parameters were assessed at baseline, week 4 (W4), end of treatment (EOT), and after EOT. The FIB-4 score and CKD-EPI equation were used to estimate liver disease and glomerular filtration rate (eGFR), respectively. For sofosbuvir, sofosbuvir metabolite (GS-331007), and daclatasvir, Ctrough was measured at W4 and week 8 (W8), and the mean of the values at those two time points (mean-Ctrough) was calculated. The Mann-Whitney test and Spearman's rank correlation were used to evaluate the correlations between the mean-Ctrough of each direct-acting antiviral (DAA) and the considered variables. RESULTS: Thirty-five patients were included (SVR 94%). An increased GS-331007 mean-Ctrough was significantly correlated with a decreased eGFR at W4 (rho = -0.36; p = 0.037) and EOT (rho = -0.34; p = 0.048). There was a significant correlation between daclatasvir mean-Ctrough and FIB-4 at all time points: baseline (rho = -0.35; p = 0.037), W4 (rho = -0.44; p = 0.008), EOT (rho = -0.40; p = 0.023), and after EOT (rho = -0.39; p = 0.028). CONCLUSIONS: In HIV/HCV-coinfected patients in a real-world setting, exposure to a high GS-331007 Ctrough was associated with a slight decrease in renal function, while advanced hepatic impairment was significantly associated with a lower daclatasvir Ctrough. Though the clinical and therapeutic relevance of these findings may be limited, increasing clinicians' knowledge regarding DAA exposure in difficult-to-treat patients could be relevant in single cases, and further investigations are warranted.
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Antivirales/farmacocinética , Carbamatos/farmacocinética , Infecciones por VIH , Hepatitis C Crónica , Imidazoles/farmacocinética , Pirrolidinas/farmacocinética , Sofosbuvir/farmacocinética , Valina/análogos & derivados , Antivirales/sangre , Área Bajo la Curva , Carbamatos/sangre , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Imidazoles/sangre , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Pirrolidinas/sangre , Sofosbuvir/sangre , Valina/sangre , Valina/farmacocinéticaRESUMEN
PURPOSE: Low vitamin D levels are associated with higher odds of cognitive dysfunction in the older population, and in subjects with mental disorders or with chronic neurologic diseases. With combination antiretroviral therapy (cART), incidence of HIV-associated dementia has reduced, while the prevalence of milder forms of neurocognitive impairment (NCI) persisted stable over time. Hypovitaminosis D is often found in HIV infection but its association with NCI has not been investigated yet. The aim was to explore this association in a clinic-based HIV-positive population. METHODS: A retrospective, cross-sectional analysis of an existing monocenter dataset obtained from patients undergoing neuropsychological assessment in routine clinical care between January, 2011 and December, 2016 was carried out. NCI was assessed through a standardized battery of 13 tests on 5 different cognitive domains and HIV-associated neurocognitive deficit (HAND) was classified according to Frascati's criteria. Vitamin D deficiency was defined by 25 hydroxy-vitamin D 25(OH)D levels < 10 ng/mL. Logistic regression was adjusted for main associated covariates and seasonality. RESULTS: 542 patients were included: 96.7% were receiving cART, median CD4 count was 611/mmc (IQR, 421-809), HIV RNA was < 40 cp/mL in 85.8%. Median 25(OH)D was 23.2 ng/mL (IQR, 15.6-29.2), with vitamin D insufficiency 67.7% and deficiency in 9.4%. Overall, NCI was found in 37.1% and HAND in 22.7%. Compared to patients with higher vitamin D levels, subjects with vitamin D deficiency had increased proportions of NCI (52.9% versus 35.4%; p = 0.014) or of HAND (42.9% versus 24.9%; p = 0.012). Median NPZ-8 scores were significantly different based on vitamin D levels (p = 0.021). At multivariable analyses, vitamin D deficiency was the only risk factor of NCI (OR 2.05; 95% CI 1.04-4.05; p = 0.038) or of HAND (OR 2.12; 95% CI 0.99-4.54; p = 0.052). CONCLUSIONS: In HIV-positive persons, severe hypovitaminosis D was independently associated with a higher risk of neurocognitive impairment in general, and of HIV-associated neurocognitive disorders in particular. Future studies are needed to elucidate causal relationship and whether vitamin D supplementation may reverse this risk.
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Infecciones por VIH/etiología , Trastornos Neurocognitivos/epidemiología , Deficiencia de Vitamina D/epidemiología , Adulto , Antirretrovirales/uso terapéutico , Estudios Transversales , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Trastornos Neurocognitivos/inducido químicamente , Prevalencia , Estudios Retrospectivos , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Deficiencia de Vitamina D/complicacionesRESUMEN
OBJECTIVE: Antiretrovirals with long half-lives, such as tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and efavirenz (EFV), are suitable for reduced frequency dosing, with potential for improved adherence and reduced toxicity and costs. The objective of this study was to investigate the noninferiority of the TDF/FTC/EFV fixed-dose combination on alternate-days versus standard regimen in virologically suppressed patients. DESIGN: A randomized-controlled open-label noninferiority trial enrolling HIV-1-infected patients treated for at least 6 months with TDF/FTC/EFV fixed-dose combination, virologically suppressed (<40 HIV-RNA copies/ml) with EFV plasma concentrations greater than 1000âng/ml, were randomized to maintain TDF/FTC/EFV standard-of-care regimen (SOC, Arm A) or to switch to TDF/FTC/EFV on AlTernAte Days (ATAD, Arm B). METHODS: Primary end-point was the proportion of patients with less than 40 HIV-RNA copies/ml at week 48. RESULTS: One hundred and ninety-seven patients were randomized (98 in the SOC and 99 in the ATAD arm). One hundred and seventy-nine (90.3%) were men, median age 43.2 years, 133 (67.5%) MSM. CD4+ T-cell count at baseline was 706 cells/µl in SOC and 632 cells/µl in ATAD arm. At week 48, 95 (96.9%) patients in SOC and 93 (93.9%) in ATAD had a virological response (-3.0% overall risk difference, 95% CI: -8.86%/2.86%). Median change from baseline at week 48 in CD4+ T-cell count was 29.4 cells/µl (95% CI: 2.5/56.4) in SOC (Pâ=â0.008) and 61.0 cells/µl (95% CI: 32.1/89.9) in ATAD (Pâ<â0.001). Median change of EFV concentration at week 48 from baseline was -6.5âng/ml (95% CI: -103/55) in SOC (Pâ=â0.877) and -1124âng/ml (95% CI: -1375/-928) in ATAD arm (Pâ<â0.001). CONCLUSION: Despite a significant decrease of EFV exposure, TDF/FTC/EFV on ATAD was noninferior to SOC regimen through 48 weeks.
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Fármacos Anti-VIH/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Benzoxazinas/administración & dosificación , Emtricitabina/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Tenofovir/administración & dosificación , Carga Viral , Adulto , Anciano , Alquinos , Ciclopropanos , Femenino , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The NEAT001/ANRS143 trial demonstrated noninferiority of ritonavir-boosted darunavir combined with either raltegravir (RAL + DRV/r) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC + DRV/r) in HIV-positive, antiretroviral-naive adults. In post hoc analyses, however, RAL + DRV/r showed inferiority in patients with baseline CD4 <200/mm and HIV-1 RNA ≥100,000 copies per milliliter. This preplanned ancillary study was conducted to assess whether differences in adherence might explain efficacy results. SETTING: Phase III, open-label, randomized, multicenter study in 15 European countries (ClinicalTrials.gov, NCT01066962). METHODS: Seven hundred seventy-four participants self-reported adherence (modified AIDS Clinical Trials Group questionnaire) over 96 weeks [383 RAL + DRV/r (twice daily; 5 pills/day), 391 TDF/FTC + DRV/r (once daily; 4 pills/day)]. Primary endpoint was ≥95% versus <95% adherence to prescribed doses recorded (1) over the last 4 days or (2) on the visual analogue scale over the last 30 days. RESULTS: Characteristics, except age, were similar between arms; 9% had CD4 <200 cells/mm and HIV-1 RNA ≥100,000 copies per milliliter. Adherence ≥95% in the last 4 days (P = 0.029) or at the visual analogue scale (P = 0.0072) was higher with TDF/FTC + DRV/r than with RAL + DRV/r. Adherence ≥95% over the last 4 days was associated with lower probability of virological failure (P = 0.015). Adherence in patients with baseline CD4 <200 cells/mm and HIV-1 RNA ≥100,000 copies per milliliter was similar to the rest of the population, and not significantly associated with efficacy measures, with no significant differences between arms. CONCLUSION: Adherence was high and slightly better in the TDF/FTC + DRV/r than in the RAL + DRV/r arm. No convincing evidence was found that higher failure rate in the RAL + DRV/r arm in the subgroup with worse baseline viroimmunological status is caused by adherence differences.
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Antirretrovirales/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Humanos , Insuficiencia del TratamientoRESUMEN
Adherence to antiretroviral therapy (ART) is critical for successful treatment of Human Immunodeficiency Virus (HIV), but comparisons across settings are difficult because adherence is measured in different ways. We examined utility of different adherence measures for identification of patients at risk of viral failure (VF). Eight cohorts in the ART Cohort Collaboration contributed data from pharmacy refills or self-report questionnaires collected between 1996 and 2013 (N = 11689). For pharmacy data (N = 7156), we examined associations of percentage adherence during the 1st year of ART with VF (>500 copies/mL) at 1 year. For self-report data (N = 4533), we examined 28-day adherence with VF based on closest viral load measure within 6 months after questionnaire date. Since adherence differed markedly by measurement type, we defined different cut-off points for pharmacy (lower <45%, medium 45â»99%, higher 100%) and self-report (lower ≤95%, medium 96â»99%, higher 100%) data. Adjusted odds ratios (ORs) for VF in lower and medium, compared to higher adherence groups, were 23.04 (95% CI: 18.44â»28.78) and 3.84 (3.36â»4.39) for pharmacy data. For self-report data, they were 3.19 (2.31â»4.40) and 1.08 (0.80â»1.46). Both types of measure were strongly associated with VF. Although adherence measurements over longer time-frames are preferable for prediction, they are less useful for intervention.
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Myeloid derived suppressor cells (MDSC) is a heterogeneous subset of immature and mature cells of the myeloid lineage, undergoing expansion during pathologic conditions, and able to perform strong immune suppressive functions. It has been shown that cryopreservation selectively impacts the polimorphonuclear (PMN) MDSC viability and recovery, and alters the correct analysis of MDSC subsets. In laboratory practice, cryopreservation is often inevitable, in particular in multicenter studies where samples have to be shipped to a centralized laboratory. Aim of the present work was to set out a new protocol to evaluate the frequency of PMN-MDSC in thawed cells by flow-cytometry. PBMC were isolated from HIV+ patients and healthy donors, and were cryopreserved for at least ten days. After thawing, two different protocols were used: 1. standard protocol (SP) consisting of staining with the antibodies mix and then fixing with formalin 1%; 2. thawed protocol (TP) in which fixation foregoes the staining with the antibodies mix. Results showed that PMN-MDSC frequency in ex vivo PBMC evaluated by means TP was comparable to that analysed by SP, indicating that the protocol did not alter PMN-MDSC quantification in ex vivo cells. We then demonstrated that PMN-MDSC frequency in thawed PBMC tested by TP was almost identical to the frequency obtained in ex vivo cells evaluated by using SP. However, we observed that after three hours of culture post-thawing, PMN-MDSC were not assessable anymore with both SP and TP. In conclusion, we herein demonstrated that fixing PBMC soon after thawing and before antibody staining allows preservation of PMN-MDSC integrity and a reliable cells quantification. Thus, it is possible to phenotipically identify PMN-MDSC in cryopreserved PBMC, consenting adequate test precision and accuracy as well as making multicentre research more feasible.
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Criopreservación , Citometría de Flujo/métodos , Células Supresoras de Origen Mieloide , Supervivencia Celular , Células Cultivadas , Criopreservación/métodos , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Humanos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/patología , Fijación del TejidoRESUMEN
BACKGROUND: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. METHODS: All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA < 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log-rank test. RESULTS: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged > 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p < 0.001]. By multivariate analysis, females (p < 0.01) and PWID (p < 0.001), presented a longer time to ART initiation, while older people (p < 0.001), people with higher educational levels (p < 0.001), unemployed (p = 0.02) and students (p < 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. CONCLUSIONS: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability.
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Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Determinantes Sociales de la Salud , Adulto , Estudios de Cohortes , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores Socioeconómicos , Resultado del Tratamiento , Cobertura Universal del Seguro de SaludAsunto(s)
Fármacos Anti-VIH/uso terapéutico , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/epidemiología , Combinación Efavirenz, Emtricitabina y Fumarato de Tenofovir Disoproxil/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Terapia Antirretroviral Altamente Activa , Combinación Efavirenz, Emtricitabina y Fumarato de Tenofovir Disoproxil/efectos adversos , Combinación Efavirenz, Emtricitabina y Fumarato de Tenofovir Disoproxil/sangre , Femenino , VIH , Infecciones por VIH/psicología , Humanos , Masculino , Cumplimiento de la Medicación , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
Therapeutic drug monitoring may be crucial in selected clinical conditions for the management of HIV infection. In recent years, new antiretrovirals have been introduced and in particular elvitegravir (EVG) is now recommended for first-line and simplification treatment as well as dolutegravir (DTG) and rilpivirine (RPV). The aim of this study was to develop and validate a high-performance liquid chromatography-ultraviolet (HPLC-UV) method for determining EVG and new antiretrovirals DTG and RPV in human plasma. Solid-phase extraction was applied to a 600 µL plasma sample. Chromatographic separation of the three drugs and internal standard was achieved with a gradient of acetonitrile and phosphate buffer on a C18 reverse-phase analytical column with a 20 min analytical run time. EVG and DTG were detected at 265 nm and RPV at 290 nm. Mean intra- and inter-day precisions were < 10%; the mean accuracy was <15%. Extraction recovery ranged between 105 and 82% for the drugs analyzed. Calibration curves were optimized according to the expected ranges of drug concentrations in patients; the coefficient of determination was >0.997 for all drugs. This method allows for monitoring EVG, DTG and RPV in the plasma of HIV-positive patients using HPLC-UV.
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The impact of early antiretroviral therapy (ART) during Primary HIV Infection (PHI) on the hematopoietic progenitor cells (HPCs) homeostasis is not available. This study aimed to characterize HPCs and their relationship with cytokines regulating progenitors function in ART-treated patients with PHI. We enrolled HIV infected patients treated with ART during PHI. Circulating HPCs, Lymphoid-HPCs (L-HPCs) frequency and plasmatic concentrations of IL-7, IL-18 and Stem Cell Factor (SCF) were analysed at baseline and after 6â¯months of therapy. ART introduction during PHI restored the decline of L-HPCs, induced a decrease in the level of pro-inflammatory IL-18 cytokine and a parallel increase of SCF. Moreover, L-HPCs frequency positively correlated with IL-18 at baseline, and with SCF after 6â¯months of therapy, suggesting that different signals impact L-HPCs expansion and maintenance before and after treatment. Finally, the SCF receptor expression on HPCs decreased after early ART initiation. These insights may open new perspectives for the evaluation of cytokine-driven L-HPCs expansion and their impact on the homeostasis of hematopoietic compartment during HIV infection.
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Infecciones por VIH/sangre , VIH-1 , Células Madre Hematopoyéticas/metabolismo , Interleucina-18/sangre , Factor de Células Madre/sangre , Adulto , Antirretrovirales/administración & dosificación , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Células Madre Hematopoyéticas/patología , Humanos , MasculinoRESUMEN
BACKGROUND: HIV-positive patients carry an increased risk of HPV infection and associated cancers. Therefore, prevalence and patterns of HPV infection at different anatomical sites, as well as theoretical protection of nonavalent vaccine should be investigated. Aim was to describe prevalence and predictors of oral HPV detection in HIV-positive men, with attention to nonavalent vaccine-targeted HPV types. Further, co-occurrence of HPV DNA at oral cavity and at anal site was assessed. METHODS: This cross-sectional, clinic-based study included 305 HIV-positive males (85.9% MSM; median age 44.7 years; IQR: 37.4-51.0), consecutively observed within an anal cancer screening program, after written informed consent. Indication for anal screening was given by the HIV physician during routine clinic visit. Paired oral rinse and anal samples were processed for the all HPV genotypes with QIASYMPHONY and a PCR with MY09/MY11 primers for the L1 region. RESULTS: At the oral cavity, HPV DNA was detected in 64 patients (20.9%), and in 28.1% of these cases multiple HPV infections were found. Prevalence of oral HPV was significantly lower than that observed at the anal site (p < 0.001), where HPV DNA was found in 199 cases (85.2%). Oral HPV tended to be more frequent in patients with detectable anal HPV than in those without (p = 0.08). Out of 265 HPV DNA-positive men regardless anatomic site, 59 cases (19.3%) had detectable HPV at both sites, and 51 of these showed completely different HPV types. At least one nonavalent vaccine-targeted HPV type was found in 17/64 (26.6%) of patients with oral and 199/260 (76.5%) with anal infection. At multivariable analysis, factors associated with positive oral HPV were: CD4 cells <200/µL (versus CD4 cells >200/µL, p = 0.005) and >5 sexual partners in the previous 12 months (versus 0-1 partner, p = 0.008). CONCLUSIONS: In this study on Italian HIV-positive men (predominantly MSM), oral HPV DNA was detected in approximately one fifth of tested subjects, but prevalence was significantly lower than that observed at anal site. Low CD4 cell count and increasing number of recent sexual partners significantly increased the odds of positive oral HPV. The absence of co-occurrence at the two anatomical sites may suggest different routes or timing of infection.
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ADN Viral/metabolismo , Infecciones por VIH/diagnóstico , Papillomaviridae/genética , Infecciones por Papillomavirus/diagnóstico , Adulto , Canal Anal/virología , Recuento de Linfocito CD4 , Estudios Transversales , ADN Viral/aislamiento & purificación , Genotipo , Homosexualidad Masculina , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Boca/virología , Análisis Multivariante , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Reacción en Cadena de la Polimerasa , PrevalenciaRESUMEN
BACKGROUND: Possible drug-drug interactions (DDIs) between antiretrovirals (ARVs) and direct-acting antiviral agents (DAAs) are of some concern. OBJECTIVES: To investigate ARV plasma trough concentrations (Ctrough) before and during DAAs in patients treated in the real world. METHODS: Single-centre, prospective, observational study including HIV/HCV coinfected persons undergoing DAA treatment. Self-reported adherence was assessed and ARVs Ctrough measured by HPLC-UV. Blood samples were collected before and after 2 months of DAA treatment. RESULTS: One-hundred and thirty-seven patients were included: 21.2% treated with ombitasvir/paritaprevir/ritonavir ± dasabuvir (2D/3D) and 78.8% with sofosbuvir-based regimens. Suboptimal Ctrough before and during DAA was found, respectively, in 3 (10.3%) and 3 (10.3%) cases treated with 2D/3D, and 16 (14.8%) and 11 (10.2%) with sofosbuvir-based regimens, even if self-reported ARV adherence was always ≥93%. In 2D/3D-treated patients, median darunavir Ctrough during DAAs was significantly lower than observed before DAAs [1125 ng/mL (IQR, 810-1616) versus 1903 ng/mL (IQR 1387-3983), respectively] (n = 5; P = 0.009), with a 40.9% decrease. In the same group, no differences in atazanavir or raltegravir concentrations were found. In patients treated with sofosbuvir-based regimens, Ctrough of all ARVs were similar before and during DAAs. CONCLUSIONS: In the real world of HIV/HCV coinfected patients, ARV plasma concentrations during DAAs were generally not different from those found before anti-HCV treatment. Although assessed in a small number of patients, darunavir concentrations during 2D/3D showed a significant reduction when compared with those found before DAAs. ARV plasma concentrations measurement during anti-HCV treatment may give useful information for managing HIV/HCV coinfected persons receiving treatment for both infections.
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Antirretrovirales , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , 2-Naftilamina , Anilidas/sangre , Anilidas/farmacocinética , Anilidas/uso terapéutico , Antirretrovirales/sangre , Antirretrovirales/farmacocinética , Antirretrovirales/uso terapéutico , Carbamatos/sangre , Carbamatos/farmacocinética , Carbamatos/uso terapéutico , Coinfección/tratamiento farmacológico , Ciclopropanos , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Lactamas Macrocíclicas , Compuestos Macrocíclicos/sangre , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/uso terapéutico , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Estudios Prospectivos , Ritonavir/sangre , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Sofosbuvir/sangre , Sofosbuvir/farmacocinética , Sofosbuvir/uso terapéutico , Sulfonamidas/sangre , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Resultado del Tratamiento , Uracilo/análogos & derivados , Uracilo/sangre , Uracilo/farmacocinética , Uracilo/uso terapéutico , ValinaRESUMEN
Direct-acting antiviral agents (DAAs) represent the major advance in hepatitis C virus (HCV) infection treatment leading to extremely high eradication rates in HCV mono- and HIV/HCV co-infected patients. In this scenery, availability of Therapeutic Drug Monitoring (TDM) is of interest to assess plasma concentrations to prevent either therapeutic failure due to suboptimal medication adherence and drug-drug interactions or avoid adverse events. Aim of this study was to develop and validate an Ultra-Performance Liquid Chromatography Mass Spectrometry (UPLC-MS/MS) method for the simultaneous quantification of sofosbuvir, sofosbuvir metabolite (GS-331007), and daclatasvir in human plasma. A simple protein precipitation was applied by adding 200⯵L acetonitrile with internal standard 6,7-Dimethyl- 2,3-di(2-pyridyl) quinoxaline to 100⯵L plasma sample. Drug separation was performed on analytical C-18 Luna Omega column (50â¯mmâ¯×â¯2.1â¯mm I.D.) with particle size of 1.6⯵m. The mobile phase consisting of water containing 0.1% formic acid and acetonitrile at flow 0.4â¯mL/min and a gradient run time of 3.5â¯min. The injection volume was 10⯵L. Anti-HCV drugs were detected in positive electrospray ionization mode. The full scan mass spectral analyses of sofosbuvir, GS-331007, daclatasvir and quinaxoline showed protonated molecule ions and transitions m/z: 530.098â¯ââ¯243.02, 260.93â¯ââ¯112.94, 739.4â¯ââ¯339.27 and 313.03â¯ââ¯77.99 respectively. The linearity of standard curves was excellent (r2â¯>â¯0.99), the absolute recovery of anti-HCV drugs ranged between 95 and 98%, and both imprecision and inaccuracy were <15% according to FDA guidelines. The UPLC-MS/MS method was applied to 16 plasma samples of as many HIV/HCV co-infected patients treated with sofosbuvir and daclatasvir. While sofosbuvir was not detectable in all samples, the median plasma concentrations of daclatasvir and GS-331007 were 223.6⯱â¯319.56â¯ng/mL and 537.11⯱â¯242.09â¯ng/mL, respectively. In conclusion, we describe an UPLC-MS/MS method allowing the simultaneous quantification of sofosbuvir, GS-331007 and daclatasvir in plasma samples. The method was sensitive, specific, robust, and time-saving.
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Antivirales/sangre , Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Imidazoles/sangre , Sofosbuvir/sangre , Carbamatos , Cromatografía Líquida de Alta Presión/métodos , Humanos , Límite de Detección , Modelos Lineales , Pirrolidinas , Reproducibilidad de los Resultados , Sofosbuvir/análogos & derivados , Sofosbuvir/química , Espectrometría de Masas en Tándem/métodos , Valina/análogos & derivadosRESUMEN
In Italy the prevalence of recent HIV infection (RHI) isn't currently monitored. Early diagnosis is crucial to allow introduction of antiretroviral therapy (cART) in the recent phase of infection. We aimed to estimate the proportion and the determinants of RHI among patients enrolled in the ICONA cohort; we explored differences in the median time from HIV diagnosis to cART initiation and in the viro-immunological response between RHI and Less Recent HIV infections (NRHI). We included antiretroviral-naïve HIV-positive patients enrolled in the cohort with documented dates of HIV-negative and positive antibodies tests, grouped in RHI (estimated date of seroconversion within 12 months of enrolment) and NRHI. Proportion of RHI and the trend of this proportion by calendar period (1996-2014) were investigated (Chi-square test). Logistic regression analysis was employed to identify factors associated with RHI. The time from seroconversion to cART initiation was compared in RHI and NRHI overall and after stratification by calendar period (survival analysis). We finally explored the time from starting cART to HIV-RNA <50 copies/mL and to CD4+ gain ≥200 cells/mmc by Cox regression. HIV seroconversion could be estimated for 2608/12,616 patients: 981/2608 (37.6%) were RHI. Proportion of RHI increased in recent calendar periods and was associated with younger age, baseline higher HIV-RNA and CD4+ count. There wasn't difference in the 2-year estimates of cART start between RHI and NRHI, regardless of calendar period. Rates and hazards of virological response were similar in RHI versus NRHI. RHI showed a 1.5-fold higher probability of CD4+ gain, also following adjustment for calendar period and cART regimen, and for age, HCV and smoking; the difference in probability was however attenuated after further controlling for baseline HIV-RNA and CD4+ T-cells. The increased proportion of RHI over time suggests that in recent years in Italy HIV infections are more likely to be detected earlier than before. The similar rates of cART introduction and viro-immunological response in RHI and NRHI probably reflect the efficacy of the modern cART regimens. An improvement of the prevention services is warranted to allow an early cART access, also in the perspective of therapy as prevention.
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Infecciones por VIH/epidemiología , Seroprevalencia de VIH/tendencias , Adulto , Fármacos Anti-VIH/uso terapéutico , Estudios de Cohortes , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Italia/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
Persistent residual viremia (RV) has been demonstrated in 70-90% of patients under successful cART. We analyzed the RV trend during the first year following cART-induced virological suppression (VS; HIVRNA <50 copies/ml) to identify predictors of achievement and maintenance of ultra-deep RV suppression (URVS; HIV-RNA <5 copies/ml) in 60 naïve patients. These patients were aligned at the time of reaching VS and were longitudinally tested with an ultrasensitive HIV-RNA assay. The influence of demographics, primary/chronic infection, pre-therapy HIV-RNA and CD4, cART regimen and time to reach VS on RV trends was evaluated. During the first year following VS, median RV levels steadily decreased. RV dropped below 5 copies/ml at least once in each patient, but URVS was maintained in 45% of patients. RV rebounded to levels fluctuating around 5-10 copies/ml while in the remaining 55% of patients. Predictors of early achievement and maintenance of stable URVS were fast (<12 weeks) VS achievement after the start of therapy, better pre-treatment viro-immunological conditions (lower viremia and higher CD4 before cART), and treatment initiation during primary infection. These findings emphasize the importance of an early onset of potent antiretroviral regimens. RV trends should be further studied in detail in the following years of cART.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Viremia/tratamiento farmacológico , Terapia Antirretroviral Altamente Activa , Femenino , Infecciones por VIH/virología , Humanos , Masculino , Estudios Prospectivos , ARN Viral/sangre , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: Aim was to determine the dynamics of peripheral blood mononuclear cells (PBMC)- associated total HIV-1 DNA in successfully ART-treated HIV/HCV co-infected patients receiving DAA treatment and to explore possible virological hypotheses underlying the phenomenon. METHODS: Longitudinal, single-centre study measuring total HIV-1 DNA before the start of DAA, at the end of treatment (EOT), and 3 months after treatment. Univariable and multivariable analyses were used to assess factors associated with HIV-1 DNA increase ≥0.5 Log copies/million PBMC. Episomal 2-LTR forms, residual HIV-1 viremia and proviral DNA quasispecies evolution were also investigated. RESULTS: 119 successfully ART-treated HIV/HCV co-infected patients were included. Median baseline HIV-1 DNA was 3.84 Log copies/million PBMC (95%CI 3.49-4.05), and no significant variation with respect to baseline was found at EOT and after 3 months of DAA termination. In 17% of cases an increase ≥0.5 Log copies/million PBMC was observed at EOT compared to baseline. HIV-1 DNA increase was independently associated with lower baseline HIV-1 DNA, longer HIV suppression, raltegravir-based ART and previous exposure to interferon/ribavirin for HCV treatment. In none of the patients with HIV-1 DNA increase, 2-LTR forms were detected at baseline, while in 2 cases 2-LTR forms were found at EOT, without association with residual HIV-1 RNA viremia. No evidence of viral evolution was observed. CONCLUSIONS: In successfully ART-treated HIV/HCV co-infected patients receiving DAA, PBMC-associated total HIV-1 DNA was quite stable over time, but some patients showed a considerable increase at EOT when compared to baseline. A significantly higher risk of HIV DNA increase was found, in presence of lower cellular HIV reservoir at baseline. Activation of replicative-competent virus generating new rounds of viral replication seems unlikely, while mobilization of cell-associated HIV from tissue reservoirs could be hypothesized.
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ADN Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Hepatitis C/tratamiento farmacológico , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Duplicado del Terminal Largo de VIH , Hepatitis C/complicaciones , Hepatitis C/virología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , FilogeniaRESUMEN
OBJECTIVE: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. METHODS: HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. RESULTS: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. DISCUSSION: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.