ABSTRACT
BACKGROUND: Anal squamous cell carcinoma is rare, in general, but considerably higher in HIV-infected men who have sex with men. There is no consensus on the screening of at-risk populations. OBJECTIVE: This study aimed to determine the incidence rates of anal squamous cell carcinoma and the efficacy of a screening program. DESIGN: This is a cohort study (SeVIHanal/NCT03713229). SETTING: This study was conducted at an HIV outpatient clinic in Seville, Spain. PATIENTS: From 2004 to 2017, all patients with at least 1 follow-up visit were analyzed (follow-up group), including a subgroup of men who have sex with men who participated in a specialized program for screening and treating anal neoplasia (SCAN group) from 2011 onward. MAIN OUTCOME MEASURES: The primary outcome measure was the incidence rate of anal squamous cell carcinoma. RESULTS: Of the 3878 people living with HIV included in the follow-up group, 897 were transferred to the SCAN group; 1584 (41%) were men who have sex with men. Total follow-up was 29,228 person-years with an overall incidence rate for anal squamous cell carcinoma of 68.4/100,000 person-years (95% CI, 46.7-97.4). The changes in the incidence rate/100,000 person-years (95% CI) over time was 20.7 (3.40-80.5) for 2004 to 2006, 37.3 (13.4-87.3) for 2007 to 2010, and 97.8 (63.8-144.9) for 2011 to 2017 (p < 0.001). The strongest impact on the incidence of anal squamous cell carcinoma was made by the lack of immune restoration (adjusted incidence rate ratio (95% CI): 6.59 (4.24-10); p < 0.001), the Centers for Disease Control and Prevention category C (adjusted incidence rate ratio (95% CI): 7.49 (5.69-9.85); p < 0.001), and non-men who have sex with men (adjusted incidence rate ratio (95% CI): 0.07 (0.05-0.10); p < 0.001) in a Poisson analysis. From 2010 to 2017, incidence rates (95% CI) of anal squamous cell carcinoma within the SCAN group and the men who have sex with men of the follow-up group were 95.7 (39.6-202) and 201 (101-386)/100,000 person-years (adjusted incidence rate ratio (95% CI): 0.30 (0.23-0.39); p<0.001). The incidence rate ratio (95% CI) including non-men who have sex with men in the follow-up group was 0.87 (0.69-1.11); p = 0.269. LIMITATIONS: Adherence to the visits could not be quantified. CONCLUSION: Incidence rates of anal squamous cell carcinoma in people living with HIV increased significantly from 2004 to 2017, especially in men who have sex with men who were not being screened. Participation in the SCAN program significantly reduced the incidence of anal squamous cell carcinoma in men who have sex with men, in whom focus should be placed, especially on those presenting with Centers for Disease Control and Prevention category C and advanced immune suppression. See Video Abstract at http://links.lww.com/DCR/B734. TASA DE INCIDENCIA Y FACTORES DE RIESGO DEL CARCINOMA ANAL A CLULAS ESCAMOSAS EN UNA COHORTE DE PERSONAS QUE VIVEN CON EL VIH DE A IMPLEMENTACIN DE UN PROGRAMA DE DETECCIN: ANTECEDENTES:El carcinoma anal a células escamosas es generalmente raro, pero considerablemente más alto en hombres infectados por el VIH que tienen relaciones sexuales con hombres. No hay consenso sobre el cribado de poblaciones en riesgo.OBJETIVO:Este estudio tuvo como objetivo determinar las tasas de incidencia del carcinoma anal a células escamosas y la eficacia de un programa de detección.DISEÑO:Estudio de cohorte (SeVIHanal / NCT03713229).AJUSTE:Clínica ambulatoria de VIH en Sevilla, España.PACIENTES:De 2004 a 2017, se analizaron todos los pacientes con al menos una visita de seguimiento (grupo F / U), incluido un subgrupo de hombres que tenían relaciones sexuales con hombres que participaron en un programa especializado de cribado y tratamiento de neoplasias anales (SCAN-group) a partir de 2011.PRINCIPALES MEDIDAS DE RESULTADO:Tasas de incidencia del carcinoma anal a células escamosas.RESULTADOS:De las 3878 personas que viven con el VIH incluidas en el grupo F / U, 897 fueron transferidas al grupo SCAN, 1584 (41%) eran hombres que tenían relaciones sexuales con hombres. El seguimiento total fue de 29228 personas-año con una tasa de incidencia general de carcinoma anal a células escamosas de 68,4 / 100000 personas-año [intervalo de confianza del 95%: 46,7-97,4]. El cambio en las tasas de incidencia / 100000 personas-año (intervalo de confianza del 95%) a lo largo del tiempo fue 20,7 (3,40-80,5) para 2004-2006, 37,3 (13,4-87,3) para 2007-2010 y 97,8 (63,8-144,9) para 2011-2017, p <0,001. El impacto más fuerte en la incidencia del carcinoma a células escamosas anal fue la falta de restauración inmunológica [índice de tasa de incidencia ajustado (intervalo de confianza del 95%): 6,59 (4,24-10); p <0,001], categoría C de los Centros de Control de Enfermedades [índice de tasa de incidencia ajustado (intervalo de confianza del 95%): 7,49 (5,69-9,85); p <0,001] y no hombres que tenían relaciones sexuales con hombres [razón de tasa de incidencia ajustada (intervalo de confianza del 95%): 0,07 (0,05-0,10); p <0,001] en el análisis de Poisson. Desde 2010-2017, las tasas de incidencia (intervalo de confianza del 95%) de carcinoma anal a células escamosas dentro del grupo SCAN y los hombres que tienen relaciones sexuales con hombres del grupo F / U fueron 95,7 (39,6-202) y 201 (101- 386) / 100000 personas-año [razón de tasa de incidencia ajustada (intervalo de confianza del 95%): 0,30 (0,23-0,39); p <0,001]. La razón de la tasa de incidencia (intervalo de confianza del 95%), incluidos los no hombres que tenían relaciones sexuales con hombres en F / U, fue de 0,87 [0,69-1,11); p = 0,269].LIMITACIONES:No se pudo cuantificar la adherencia a las visitas.CONCLUSIÓNES:La tasa de incidencia del carcinoma anal a células escamosas en personas que viven con el VIH aumentó significativamente de 2004 a 2017, especialmente en hombres que tenían relaciones sexuales con hombres que no se someten a pruebas de detección. La participación en el programa SCAN redujo significativamente la incidencia de carcinoma anal a células escamosas en hombres que tenían relaciones sexuales con hombres, en quienes se debe prestar una especial atención, sobre todo en aquellos que se presentan en la categoría C de los Centros de Control de Enfermedades con inmunodeficiencia avanzada. Consulte Video Resumen en http://links.lww.com/DCR/B734.
Subject(s)
Anus Neoplasms/pathology , Carcinoma, Squamous Cell/diagnosis , HIV Infections/complications , Mass Screening/methods , Adult , Carcinoma, Squamous Cell/epidemiology , Case-Control Studies , Cohort Studies , Efficiency, Organizational/statistics & numerical data , Female , Follow-Up Studies , HIV/isolation & purification , HIV Infections/epidemiology , HIV Infections/virology , Humans , Incidence , Male , Middle Aged , Neoplasm Staging/methods , Risk Factors , Sexual and Gender Minorities/statistics & numerical data , Spain/epidemiologyABSTRACT
The activation phenotypes and functional changes in monocyte subsets during hepatitis C virus (HCV) elimination in HIV/HCV-coinfected patients were evaluated. Twenty-two HIV/HCV-coinfected patients on suppressive combination antiretroviral treatment (cART) achieving HCV elimination after direct-acting antiviral (DAA) therapy and 10 HIV-monoinfected patients were included. The activation phenotype (10 markers) and polyfunctionality (intracellular interleukin-1α [IL-1α], IL-1ß, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], and IL-10 production) in three monocyte subsets (classical, intermediate, and nonclassical) were evaluated by flow cytometry before and at the end of treatment. Cell-associated HIV DNA levels were assayed by droplet digital PCR. After HCV clearance, there was a significant increase in classical monocyte and decreases in intermediate and nonclassical monocyte levels. The levels of the activation markers CD49d, CD40, and CX3CR1 were decreased after treatment in the monocyte subsets, reaching the levels in HIV-monoinfected patients. After lipopolysaccharide (LPS) stimulation, although polyfunctionality significantly decreased in intermediate and nonclassical monocytes, some combinations, such as the IL-1α- (IL-1α-negative) IL-1ß- IL-6+ (IL-6-producing) IL-8- TNF-α- IL-10- combination, were remarkably increased at the end of treatment compared to the control group. Cell-associated HIV DNA levels correlated with activation markers before but not after treatment. HCV clearance after DAA treatment in patients on cART exerts an anti-inflammatory profile on monocyte subsets, activation phenotypes, and polyfunctionality. However, there is not a complete normalization compared with HIV-monoinfected patients.
Subject(s)
Coinfection , HIV Infections , Hepatitis C, Chronic , Hepatitis C , Antiviral Agents/therapeutic use , Coinfection/drug therapy , HIV Infections/complications , HIV Infections/drug therapy , Hepacivirus , Hepatitis C/drug therapy , Hepatitis C, Chronic/drug therapy , Humans , MonocytesABSTRACT
OBJECTIVES: To analyse whether integrase inhibitor (InSTI)-based regimens achieve better immunological recovery than NNRTI- or boosted PI (bPI)-based regimens as initial ART. METHODS: In a retrospective analysis, we selected patients who initiated ART with two NRTIs plus an InSTI, an NNRTI or a bPI and maintained both the same 'third drug' and an HIV-RNA <50 copies/mL in ≥95% of determinations once undetectable viral load had been achieved. We compared CD4+ count, %CD4+ and CD4+/CD8+ ratio recovery over 2 years. Data were analysed using mixed-effects regression models for repeated measures. RESULTS: Of the 836 patients included, 208, 481 and 147 initiated with InSTI, NNRTI and bPI, respectively. For CD4+, %CD4+ and CD4+/CD8+ two main slopes were identified: from month 0 to month 6, with the highest increments; and from month 6 to month 24, with smaller increases every semester. Although the patients on InSTI achieved undetectable viral load faster, for CD4+ and %CD4+ there were no differences in the slopes of change according to the third drug either for the first phase (P=0.137 and P=0.393, respectively) or from month 6 onwards (P=0.834 and P=0.159, respectively). The increase in CD4+/CD8+ was slightly higher for bPI compared with InSTI (difference of 0.0119, 95% CI 0.0020-0.0205; P=0.018), but clinically negligible. From month 6 onwards, no differences were found between treatment groups (P=0.176). CONCLUSIONS: Immune restoration measured as CD4+ count, %CD4+ and CD4+/CD8+ increases was independent of the third antiretroviral drug class used when given with two NRTIs.
Subject(s)
HIV Infections/drug therapy , HIV Infections/immunology , HIV Integrase Inhibitors/therapeutic use , HIV Protease Inhibitors/therapeutic use , Immune Reconstitution , Reverse Transcriptase Inhibitors/therapeutic use , Adult , CD4 Lymphocyte Count , CD4-CD8 Ratio , Female , Humans , Male , Middle Aged , Retrospective Studies , Viral Load/drug effectsABSTRACT
BACKGROUND: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). METHODS: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014-2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen). RESULTS: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients (all with baseline VL ≥ 50 copies/ml) changed due to virological failure. CONCLUSIONS: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads.
Subject(s)
Anti-HIV Agents/therapeutic use , Drug Therapy, Combination/standards , HIV Infections/drug therapy , HIV-1/drug effects , Viral Load/drug effects , Adult , Cobicistat/therapeutic use , Darunavir/therapeutic use , Emtricitabine/therapeutic use , Female , Humans , Male , Middle Aged , Quinolones/therapeutic use , Spain , Tenofovir/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: Screening methods for anal squamous intraepithelial lesions (SILs) are suboptimal. We aimed to determine the diagnostic performance of a composite endpoint comprising anal liquid-based cytology (aLBC) and high-risk human papillomavirus (HR-HPV) testing to predict histological high-grade SILs (hHSILs). METHODS: From the SeVIHanal cohort, human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) who had an aLBC with concomitant HR-HPV testing were included. hHSILs were determined by high-resolution anoscopy (HRA)-guided biopsy. RESULTS: A total of 705 visits obtained from 426 patients were included. The prevalence of HR-HPV among aLBC results were 51.9% (133/215) normal, 87.9% (20/232) low-grade SILs (LSILs), and 90.9% (149/164) high-grade SILs; P (linear association) < .001. Low prevalence of hHSILs was only observed for the composite aLBC/HR-HPV testing endpoint "normal/noHR-HPV" (10%) and "LSIL/noHR-HPV" (4%). The prognostic values (95% confidence interval) for HR-HPV to predict hHSILs in normal cytology were positive predictive value (PPV), 29.3% (25.6%-33.3%); negative predictive value (NPV), 90.2% (82.8%-94.7%); sensitivity, 83% (69.2%-92.4%); and specificity, 44.1% (36.4%-51.9%). Corresponding figures for cytologic LSILs were PPV, 39.2% (37.4%-41.1%); NPV, 96.4% (78.9%-99.5%); sensitivity, 98.8% (93.3%-99.9%); and specificity, 17.9% (12.1%-24.9%). A positive interaction and a synergistic effect for the composite endpoint were observed (relative excess risk = 1.50, attributable proportion of histological results to interaction = 0.17, synergy index = 1.24). CONCLUSIONS: HRA should not be indicated in the setting of LSILs/noHR-HPV following aLBC-based screening. In contrast, HIV-infected MSM with normal aLBC/HR-HPV infection should be considered for HRA. CLINICAL TRIALS REGISTRATION: NCT03713229.
Subject(s)
Anus Neoplasms/epidemiology , Anus Neoplasms/etiology , Carcinoma in Situ/epidemiology , Carcinoma in Situ/etiology , HIV Infections/epidemiology , Homosexuality, Male , Papillomavirus Infections/diagnosis , Papillomavirus Infections/virology , Adult , Algorithms , Anus Neoplasms/diagnosis , Biopsy , Carcinoma in Situ/diagnosis , Cytodiagnosis , Disease Management , HIV Infections/complications , HIV Infections/virology , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Odds Ratio , Papillomaviridae/classification , Papillomaviridae/genetics , Papillomavirus Infections/complications , Papillomavirus Infections/epidemiology , Proctoscopes , Reproducibility of Results , Risk Assessment , Sensitivity and SpecificityABSTRACT
Viremic nonprogressors (VNPs) constitute a very scarce group of untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain stable CD4+ T cell counts despite high levels of HIV-1 replication. The specific factors associated with this atypical control of the HIV infection have been poorly described. Since specific T cell responses seem to be one of the main causes of HIV-1 control in elite controllers, we studied whether HIV-1 Gag-specific cytotoxic T lymphocyte (CTL) responses could also modulate disease control in VNPs. We characterized the immune responses from four VNPs compared to those of five standard progressors (SPs) during the first years of HIV-1 infection. We observed no differences in the breadth and frequency of Gag-specific cellular responses. Furthermore, we obtained 217 HIV-1Gag clonal sequences in which the viral variability of Gag increased over 3 years of infection for synonymous and nonsynonymous mutations in both VNPs and SPs. VNPs evolution rates in gag were comparable to SPs. This observation is in line with a similar accumulation of CTL putative escape mutations in Gag epitopes targeted by CTL responses. Altogether, the absence of viral pathogenesis in VNP individuals seems to be independent of HIV-Gag-specific CTL responses. This novel information guides to the study of alternative mechanism of HIV-1 pathogenesis control.IMPORTANCE Control of HIV infection has been widely studied in elite controllers or long-term nonprogressor models. However, there is a less-known group of individuals, termed viremic nonprogressors (VNPs), who maintain stable CD4+ T cell counts despite high plasma viremia. The mechanisms involved in this remarkable control of HIV-1 pathogenesis clearly have implications for the development of new drugs and vaccines. We show here for the first time that VNPs have immune responses and HIV-gag evolution similar to those of standard progressors. Remarkably, we demonstrate that the mechanism of pathogenesis control in these individuals differs from some elite controllers that are reported to have improved immune control. This is noteworthy since it opens the door to new, as-yet-unknown mechanisms for HIV control. Our novel results advance the understanding of mechanisms involved in viremic nonprogression and suggest that there are alternative mechanisms to the adaptive immune responses for an effective control of viral pathogenesis.
Subject(s)
CD4-Positive T-Lymphocytes/virology , HIV Infections/pathology , HIV-1/immunology , T-Lymphocytes, Cytotoxic/immunology , Viremia/immunology , gag Gene Products, Human Immunodeficiency Virus/immunology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , HIV Infections/blood , HIV Infections/immunology , HIV Infections/virology , HIV-1/pathogenicity , Humans , Viral Load , Viremia/virology , Virus Replication/immunology , gag Gene Products, Human Immunodeficiency Virus/geneticsABSTRACT
Background: There are contradictory data about the influence that hepatitis C virus (HCV) has on immune activation and inflammation in patients coinfected with human immunodeficiency virus (HIV) and HCV. Methods: HIV/HCV-coinfected patients receiving antiretroviral treatment who achieved a sustained virological response with interferon-free regimens were consecutively enrolled in a prospective study. The following factors were assessed before, immediately after the end of, and 1 month after the end of therapy: expression of HLA-DR/CD38, PD-1, and CD57 on CD4+ and CD8+ T-cells; measurement of the total HIV DNA load in peripheral blood mononuclear cells; and determination of plasma levels of soluble CD14 (sCD14), lipopolysaccharide (LPS), 16S ribosomal DNA (rDNA), interleukin 6 (IL-6), D-dimers, and high-sensitivity C-reactive protein (hsCRP). Results: Ninety-seven patients were consecutively included. At the end of therapy and 1 month later, there were significant reductions in the expression of HLA-DR and CD38 in CD4+ and CD8+ T cells, as well as levels of proviral HIV DNA, sCD14, LPS, 16S rDNA, and D-dimer (P < .001). By contrast, the expression of PD-1 and CD57 in CD4+ and CD8+ T cells and levels of IL-6 and hsCRP did not change. The improvement in levels of immune activation markers, proviral HIV DNA, and microbial translocation markers did not translate into an increased CD4+ T-cell count or increased ratio of the CD4+ T-cell count to the CD8+ T-cell count. Conclusions: HCV eradication in HIV/HCV-coinfected patients results in significant decreases in levels of immune activation markers, proviral HIV DNA load, microbial translocation markers, and D-dimers. These findings support the use of HCV treatment for all HIV/HCV-coinfected patients, even those with low-grade fibrosis.
Subject(s)
Antiviral Agents/therapeutic use , Bacterial Translocation , Coinfection/pathology , HIV Infections/pathology , HIV/isolation & purification , Hepatitis C, Chronic/drug therapy , Viral Load , Biomarkers/analysis , Coinfection/virology , Female , HIV/immunology , HIV Infections/complications , HIV Infections/virology , Hepatitis C, Chronic/complications , Humans , Immunologic Factors/analysis , Male , Middle Aged , Prospective Studies , RNA, Bacterial/genetics , RNA, Ribosomal, 16S/genetics , Sustained Virologic Response , T-Lymphocytes/chemistry , T-Lymphocytes/immunology , Treatment OutcomeABSTRACT
BACKGROUND: There are several regimens for starting antiretroviral treatment, but it remains unknown whether either of them is more advantageous regarding the time course and magnitude of human immunodeficiency virus (HIV) RNA decay in semen. OBJECTIVE: To evaluate the differential effect of different antiretroviral drug families on viral kinetics in seminal plasma (SP) of treatment-naive HIV-infected patients. METHODS: Phase II, randomized, open-label study in which participants were randomized 1:1:1 to receive tenofovir-disoproxil fumarate (DF) plus emtricitabine, and either cobicistat-boosted elvitegravir (EVGcobi), rilpivirine (RPV), or ritonavir-boosted darunavir (DRVrtv). The primary endpoint was the proportion of participants with undetectable HIV-RNA in SP at week 12. HIV type 1 (HIV-1) RNA was measured in paired SP and blood plasma (BP) at baseline and after 1, 2, 4, 6, 8, 12, 18, and 24 weeks. Elvitegravir (EVG), RPV, and darunavir (DRV) concentrations were quantified by the liquid chromatography-tandem mass spectrometry method. RESULTS: In SP, the HIV-RNA decay rate with RPV was as fast as with EVGcobi; by week 12, all participants in the RPV and the EVGcobi groups reached an undetectable viral load but only 58.3% in the DRVrtv arm (P = .003). The highest SP/BP drug concentration ratio was for EVG (0.43), followed-up by RPV (0.19), and DRV (0.10). For both EVG and RPV, the SP concentrations exceeded >2-fold the protein binding-adjusted EC90 for wild-type HIV-1; for DRV, only 33.7% of the SP showed concentrations above the protein binding-adjusted EC90. CONCLUSIONS: In SP, both RPV and EVGcobi, associated to tenofovir-DF and emtricitabine, behave similarly and achieve an undetectable viral load much faster than DRVrtv. REGISTRATION: European Medical Agency (No. EudraCT: 2014-001348-39).
Subject(s)
Anti-Retroviral Agents/therapeutic use , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/physiology , Semen/virology , Adult , HIV Infections/epidemiology , Humans , Kinetics , Male , Middle Aged , RNA, Viral/analysis , RNA, Viral/blood , RNA, Viral/chemistry , Viral Load , Young AdultABSTRACT
Objectives: To evaluate if there are significant drug-drug interactions between cobicistat-boosted elvitegravir and 800 mg darunavir once daily taken simultaneously, as has been suggested previously. Methods: The study population consisted of three groups of unselected volunteers taking a regimen of elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate (150, 150, 200 and 300 mg, respectively) co-formulated in a single tablet plus 800 mg darunavir (group A); only co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate (group B); and cobicistat-boosted darunavir (800 mg darunavir + 150 mg cobicistat) plus two nucleos(t)ide analogues (group C). Elvitegravir, cobicistat and darunavir concentrations at the end of the dosing interval ( C 24 ) were quantified using a validated LC with tandem MS method. Results: A total of 170 samples were obtained from 24, 32 and 32 patients in groups A, B and C, respectively. In group A, the elvitegravir C 24 were similar to those in group B (233.67 versus 250.39 ng/mL) ( P = 0.406) and the darunavir C 24 were similar to those in group C (1293.54 versus 1319.34 ng/mL) ( P = 0.908). The cobicistat C 24 were comparable in groups A and B (20.2 versus 20.9 ng/mL) and slightly higher in group C (27.7 ng/mL) ( P = 0.059). Conclusions: The results provide evidence of similar elvitegravir and darunavir C 24 concentrations when these drugs are co-administered as co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate plus 800 mg darunavir or dosed separately.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Cobicistat/administration & dosage , Darunavir/pharmacokinetics , HIV Infections/drug therapy , Quinolones/pharmacokinetics , Adult , Aged , Aged, 80 and over , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Cobicistat/therapeutic use , Darunavir/administration & dosage , Darunavir/therapeutic use , Drug Combinations , Drug Interactions , Female , HIV Infections/virology , HIV-1/drug effects , Humans , Male , Middle Aged , Quinolones/administration & dosage , Quinolones/therapeutic use , Young AdultABSTRACT
BACKGROUND: Plasma HIV p24 is considered a significant predictor of CD4+ T cell decline and progression to AIDS in HIV-infected patients. We evaluated the p24 levels in patients on triple therapy and after switching to ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv), as well as the relationships with virological and immunological evolution. MATERIALS AND METHODS: Plasma samples from patients participating in two studies of simplification to mtPI/rtv were analysed for presence of p24, using a boosted enzyme-linked immunosorbent assay specific for mature p24. Only patients with available samples at baseline (on triple therapy) and during a follow-up of at least 12 months after switching to mtPI/rtv were included. RESULTS: A total of 233 samples from 51 patients were analysed. After switching to mtPI/rtv and a median follow-up of 24 months, 14 patients maintained continuous undetectable viraemia, and 37 patients experienced a total of 49 transient viraemic episodes. Unexpectedly, the evolutionary p24 patterns were uniform for most patients, both before and after switching to mtPI/rtv, independently of the virological behaviour, fitting into one of three categories: persistent undetectable p24 levels, positive p24, matching only with the viraemic episodes, and persistent detectable p24 levels. The last group showed lower CD4+ T cell counts and percentages, as well as lower CD4+/CD8+ T cell ratios after 12 and 24 months of follow up. CONCLUSION: Treatment simplification to mtPI/rtv does not influence the behaviour of p24 in plasma. Patients with continuous positive p24, despite undetectable viraemia, showed worse immunological evolution.
Subject(s)
CD4-Positive T-Lymphocytes , HIV Infections/drug therapy , HIV Infections/immunology , HIV Protease Inhibitors/therapeutic use , HIV-1 , Ritonavir/therapeutic use , Adult , CD4 Lymphocyte Count , Female , HIV Infections/blood , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Human immunodeficiency virus (HIV) controllers have the striking ability to maintain viremia at extremely low or undetectable levels without antiretroviral treatment. Even though these patients have been widely studied, information about clinical outcomes, especially concerning to non-AIDS-defining events (nADEs), is scarce. We have analyzed the frequency and rate of nADEs and their associated factors in a large multicenter HIV controller cohort. METHODS: Data on nADEs were recorded for 320 HIV controllers within the multicenter Spanish AIDS Research Network HIV Controllers Cohort (ECRIS). Percentages and crude incidence rates (CIRs) per 100 person-years of follow-up (PYFU) were calculated for the entire follow-up period and for 2 separate periods: the period under control and the period after loss of control. These rates were compared with those for 632 noncontrollers. Demographic and immunological data collected from the controllers were included in a multivariate model to assess factors that were independently associated with nADEs in HIV controllers. RESULTS: HIV controllers experience nADEs, albeit at lower rates than patients who do not spontaneously control the virus (1.252 [95% confidence interval {CI}, .974-1.586] per 100 PYFU and 2.481 [95% CI, 2.153-2.845] per 100 PYFU, respectively; P < .001). Hepatitis C virus (HCV) coinfection was the main factor associated with nADEs in all of the studied periods. Although hepatic events were the most prevalent, they represented only approximately 30% of the total events. CIRs of cardiovascular events increased in the post-loss-of-control period. CONCLUSIONS: HCV/HIV coinfection was the main factor associated with hepatic and extrahepatic nADEs in HIV controllers. The eradication of HCV infection may ameliorate the presence of comorbidities in these patients.
Subject(s)
HIV Infections/complications , HIV Infections/epidemiology , HIV-1 , Adult , Cardiovascular Diseases/complications , Cardiovascular Diseases/epidemiology , Coinfection , Comorbidity , HIV Infections/virology , Hepatitis C/complications , Hepatitis C/epidemiology , Humans , Middle Aged , Neoplasms/complications , Neoplasms/epidemiology , Risk Factors , Viremia/epidemiology , Viremia/virologyABSTRACT
The Perfil-es study demonstrated that, while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based initial antiretroviral therapy (ART) is more frequently used in human immunodeficiency virus (HIV)-infected naïve patients, ritonavir-boosted protease inhibitors (PI/r)-based regimens are the preferred option in patients with advanced infectious stages or high baseline viral load. The present analysis focused on the second phase of the Perfil-es study, where sociodemographic and clinical data were retrospectively collected from patients starting NNRTI- or PI/r-based regimens in order to identify factors that could influence the choice of initial ART. Patients' characteristics were compared by both bivariate and multivariate analyses. A total of 642 patients were evaluated. The main transmission group was men who have sex with men (MSM) (48%), and 24% of patients were coinfected with hepatitis B or C. Patients with cardiovascular risk accounted for 56%, and 15% had a neuropsychiatric history. Anxiolytics (29%), antidepressants (18%) and methadone (18%) were the most frequent concomitant medications. The use of PI/r-based regimens was more frequent in older patients, childbearing potential women patients coinfected with hepatitis B or C, and those with cardiovascular risk and a neuropsychiatric history. The presence of a neuropsychiatric disorder (OR: 1.912; CI 95%: 1.146-3.191; p < .05) and the use of concomitant medication (OR: 1.736; CI 95%: 1.204-2.502; p < .01) were identified as independent factors associated with the selection of PI/r-based regimens. MSM sexual conduct was the only independent factor related to the selection of NNRTI-based ART (OR: 0.699; CI 95%: 0.504-0.970; p < .05). Neither the physicians' characteristics nor the geographical area where HIV patients were attended influenced the choice of ART. In conclusion, patients' comorbidity, pregnancy potential and lifestyle seem to influence the choice of ART. Neuropsychiatric comorbidity and concomitant medication, mainly related to this condition, appear to be associated with the use of PI/r-based initial ART while MSM seem more likely to receive NNRTI-based regimens in Spain.
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Practice Patterns, Physicians' , Reverse Transcriptase Inhibitors/therapeutic use , Adult , Cardiovascular Diseases/complications , Coinfection/complications , Female , HIV Infections/complications , Hepatitis B/complications , Hepatitis C/complications , Humans , Male , Mental Disorders/complications , Mental Disorders/drug therapy , Middle Aged , Pregnancy , Retrospective Studies , Risk Factors , SpainABSTRACT
BACKGROUND: Acute hepatitis C virus (HCV) infection (AHCVI) outbreaks have been described recently within defined areas worldwide among HIV-infected homosexual men. This study aims to describe the cumulative frequency and incidence of firstly acquired AHCVI in an HIV-infected population in Southern Spain. METHODS: This is a retrospective study conducted at the Infectious Diseases Units of eight hospitals in Andalusia, Southern Spain. Primary AHC was considered as HCV immunoglobulin G antibody seroconversion. The time of infection was considered the moment between the last negative and the first positive HCV antibody determination. RESULTS: A total of 23 cases of primary AHCVI have been detected from 2000 to 2014. Incidence rates [IR; 95 % confidence interval (CI)] were 0.036 (2.272-0.054) per 100 person-years (py) in the overall population over a follow-up period of 64170 py. Of the 22 (95.7 %) male subjects, 21 (95.5 %) had acquired AHCVI by homosexual contact, the IR (95 % CI) was 0.039 (0.024-0.06) per 100 py in this subpopulation. There was no evidence of an increase of AHCVI IR. The incidence of AHCVI was slightly lower between 2000 and 2004 as compared to 2005-2009 [IR ratio (IRR) of 8.8 (95 % CI: 1.279-378.794; p = 0.01)] but reached a plateau afterwards [IRR between 2010 and 2014 versus 2005-2009: 0.727 (0.286-1.848; p = 0.5)]. The median (Q1-Q3) time between the last negative anti-HCV and the first positive anti-HCV determination was 4.7 (1.9-11.2) months. Peak (Q1-Q3) ALT and total bilirubin values during AHCVI were 496 (291-656) IU/mL and 1.15 (0.9-1.98) mg/dL, respectively. CONCLUSIONS: In contrast to what has been reported from other areas, the incidence of primary AHCVI in the HIV-infected population is stable in Southern Spain and there is no evidence of an epidemic, in spite of the high prevalence of HIV/HCV-coinfection in this area.
Subject(s)
AIDS-Related Opportunistic Infections/epidemiology , Hepatitis C/epidemiology , Adult , Coinfection/epidemiology , Disease Outbreaks , Female , HIV Infections/epidemiology , HIV Infections/microbiology , Hepatitis C/virology , Humans , Male , Middle Aged , Retrospective Studies , Spain/epidemiologyABSTRACT
IMPORTANCE: A key factor in assessing the effectiveness and cost-effectiveness of antiretroviral therapy (ART) as a prevention strategy is the absolute risk of HIV transmission through condomless sex with suppressed HIV-1 RNA viral load for both anal and vaginal sex. OBJECTIVE: To evaluate the rate of within-couple HIV transmission (heterosexual and men who have sex with men [MSM]) during periods of sex without condoms and when the HIV-positive partner had HIV-1 RNA load less than 200 copies/mL. DESIGN, SETTING, AND PARTICIPANTS: The prospective, observational PARTNER (Partners of People on ART-A New Evaluation of the Risks) study was conducted at 75 clinical sites in 14 European countries and enrolled 1166 HIV serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex (September 2010 to May 2014). Eligibility criteria for inclusion of couple-years of follow-up were condomless sex and HIV-1 RNA load less than 200 copies/mL. Anonymized phylogenetic analysis compared couples' HIV-1 polymerase and envelope sequences if an HIV-negative partner became infected to determine phylogenetically linked transmissions. EXPOSURES: Condomless sexual activity with an HIV-positive partner taking virally suppressive ART. MAIN OUTCOMES AND MEASURES: Risk of within-couple HIV transmission to the HIV-negative partner. RESULTS: Among 1166 enrolled couples, 888 (mean age, 42 years [IQR, 35-48]; 548 heterosexual [61.7%] and 340 MSM [38.3%]) provided 1238 eligible couple-years of follow-up (median follow-up, 1.3 years [IQR, 0.8-2.0]). At baseline, couples reported condomless sex for a median of 2 years (IQR, 0.5-6.3). Condomless sex with other partners was reported by 108 HIV-negative MSM (33%) and 21 heterosexuals (4%). During follow-up, couples reported condomless sex a median of 37 times per year (IQR, 15-71), with MSM couples reporting approximately 22,000 condomless sex acts and heterosexuals approximately 36,000. Although 11 HIV-negative partners became HIV-positive (10 MSM; 1 heterosexual; 8 reported condomless sex with other partners), no phylogenetically linked transmissions occurred over eligible couple-years of follow-up, giving a rate of within-couple HIV transmission of zero, with an upper 95% confidence limit of 0.30/100 couple-years of follow-up. The upper 95% confidence limit for condomless anal sex was 0.71 per 100 couple-years of follow-up. CONCLUSIONS AND RELEVANCE: Among serodifferent heterosexual and MSM couples in which the HIV-positive partner was using suppressive ART and who reported condomless sex, during median follow-up of 1.3 years per couple, there were no documented cases of within-couple HIV transmission (upper 95% confidence limit, 0.30/100 couple-years of follow-up). Additional longer-term follow-up is necessary to provide more precise estimates of risk.
Subject(s)
HIV Infections/transmission , HIV-1 , Sexual Behavior , Sexual Partners , Unsafe Sex , Adult , Anti-HIV Agents/therapeutic use , Condoms , Europe , Family Characteristics , Female , HIV Seronegativity , HIV Seropositivity , HIV-1/classification , HIV-1/enzymology , Humans , Male , Middle Aged , Phylogeny , Prospective Studies , RNA, Viral , Risk , Viral LoadABSTRACT
A higher incidence of anemia has been observed during the treatment of hepatitis C virus genotype 1 (HCV-1) infection with pegylated alpha interferon (pegIFN-α), ribavirin, and telaprevir. We assessed the impacts that concomitant administration of telaprevir and changes in the glomerular filtration rate have on ribavirin plasma levels. The minimum concentrations of ribavirin in plasma (ribavirin Cmin) determined during triple therapy including telaprevir were compared with those observed after telaprevir withdrawal and those observed in the same subjects and in a large cohort during a previous course of pegIFN-α plus ribavirin. Intensive pharmacokinetic sampling for ribavirin was performed at steady state during the triple-therapy phase. Ribavirin levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Twenty-seven HCV-1/HIV-coinfected patients were enrolled. The median ribavirin Cmin for triple therapy (4.08 µg/ml; range, 2.14 to 5.56 µg/ml) was higher than that observed after telaprevir withdrawal (1.96 µg/ml; range, 0.41 to 3.45 µg/ml) (P < 0.001) and that observed for 125 HCV-1/HIV-coinfected patients treated only with pegIFN-α plus ribavirin (1.65 µg/ml; range, 0.41 to 5.56 µg/ml) (P < 0.001). The estimated glomerular filtration rate (eGFR) decreased >20% from the baseline value in 11 of 27 patients and became normal after telaprevir removal in almost all cases. There was a negative correlation between eGFR and ribavirin clearance (r(2) = 0.257; P = 0.064) but not the ribavirin area under the concentration-time curve from 0 to 12 h (AUC0-12) (r(2) = 0.001; P = 0.455). Thus, there is a significant pharmacokinetic interaction between telaprevir and ribavirin that results in very high ribavirin levels, which explains the excess of toxicity observed with this drug combination. A blockade of the proximal tubular transporters might be implicated in both the increase in plasma creatinine and the high ribavirin levels. (This study has been registered at ClinicalTrials.gov under registration no. NCT01818856.).
Subject(s)
Antiviral Agents/pharmacokinetics , HIV Infections/drug therapy , Hepatitis C, Chronic/drug therapy , Interferon-alpha/pharmacokinetics , Oligopeptides/pharmacokinetics , Ribavirin/pharmacokinetics , Adult , Antiviral Agents/therapeutic use , Coinfection/blood , Coinfection/drug therapy , Creatinine/blood , Drug Therapy, Combination , Female , HIV Infections/blood , Hepatitis C, Chronic/blood , Humans , Interferon-alpha/therapeutic use , Male , Middle Aged , Oligopeptides/therapeutic use , Ribavirin/therapeutic use , Tandem Mass SpectrometryABSTRACT
BACKGROUND: Detrimental bidirectional pharmacokinetic interactions have been observed when telaprevir (TVR) and ritonavir (RTV)-boosted human immunodeficiency virus (HIV) protease inhibitors are coadministered in healthy volunteers. Our aim was to evaluate the role of RTV in the bidirectional TVR and atazanavir (ATV) interactions. METHOD: An open-label, sequential study was carried out in hepatitis C virus (HCV)/HIV-coinfected patients on a RTV-boosted ATV-based (ATVr) antiretroviral regimen (300/100 mg every 24 hours) and triple therapy for chronic C hepatitis genotype 1 (TVR, 1125 mg every 12 hours, pegylated interferon-alpha and ribavirin). Pharmacokinetic profiles were acquired before and after switching from ATVr to unboosted ATV (200 mg every 12 hours). The plasma levels of both drugs were determined by liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental analysis and compared by geometric mean ratios and their 90% confidence intervals. RESULTS: Fourteen white HCV/HIV-coinfected males were enrolled in this study. After RTV was withdrawn, the TVR AUC(0-12) (area under the concentration-time curve), maximum concentration (C(max)), and minimum concentration (C(min)) values increased by 19% (7%-30%), 12% (0.9%-29%), and 18% (2%-34%), respectively, without any changes in the TVR terminal half-life. The ATV AUC(0-12), C(max), and C(min) values were 39% (13%-66%), 19% (8%-59%), and 48% (1%-96%) higher, respectively, with a significantly shorter terminal half-life (22.6 hours vs 10.4 hours). CONCLUSIONS: RTV is responsible for the adverse interactions that occur when TVR and ATVr are administered together, possibly by influencing either the absorption phase or first-pass metabolism of TVR. The boost effect of TVR on ATV exposure is higher than on RTV, despite its shorter terminal half-life. The coadministration of TVR and unboosted ATV results in increased exposure of both drugs compared with their coadministration with RTV. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT01818856. European Medicines Agency EudraCT no. 2012-002515-25.
Subject(s)
Antiviral Agents/pharmacokinetics , Drug Interactions , HIV Infections/drug therapy , Hepatitis C, Chronic/drug therapy , Oligopeptides/pharmacokinetics , Pyridines/pharmacokinetics , Ritonavir/pharmacokinetics , Adult , Antiviral Agents/therapeutic use , Atazanavir Sulfate , Chromatography, Liquid , Drug Therapy, Combination/methods , HIV Infections/complications , Hepatitis C, Chronic/complications , Humans , Interferon-alpha/therapeutic use , Male , Mass Spectrometry , Middle Aged , Oligopeptides/therapeutic use , Plasma/chemistry , Pyridines/therapeutic use , Ribavirin/therapeutic use , Ritonavir/therapeutic useABSTRACT
INTRODUCTION: The purpose of Perfil-es study was to identify the proportion of patients starting ARV treatment based on NNRTIs or PI/r, and to identify the variables involved in the therapeutic decision-making in standard clinical practice. METHODS: An observational retrospective study performed in 65 Spanish hospitals. RESULTS: Was a total of 1,687 starts: 53% with NNRTI-based regimen and 42% with PI/r, and of the 642 patients analyzed, 72% had a CD4 count<350 cells/µl. CONCLUSION: The initiation of ARV treatment is still late in Spain. NNRTIs are the more frequent choice, although PI/r plays an important role.
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Anti-HIV Agents/classification , Antiretroviral Therapy, Highly Active , Drug Therapy, Combination , Drug Utilization , HIV Infections/epidemiology , HIV Protease Inhibitors/therapeutic use , HIV-1/drug effects , HIV-1/isolation & purification , Humans , Practice Guidelines as Topic , Retrospective Studies , Reverse Transcriptase Inhibitors/therapeutic use , Spain/epidemiology , Viral LoadABSTRACT
We estimated the effect of sexual behavior, age, and immunodeficiency on the number of high-risk human papillomavirus (HR-HPV) types in the anal canal among human immunodeficiency virus-positive men who have sex with men (MSM). Anal samples were genotyped with the Linear Array HPV Genotyping Test, and risk factors were investigated with Poisson regression. Of 586 MSM, 69% were Spanish, and 25.6% were Latin American; the median age was 34.9 years (interquartile range [IQR], 30.1-40.8). The median number of recent sex partners was 6 (IQR, 2-24 sex partners), and the median CD4(+) T-cell count was 531.5 cells/mm(3) (IQR, 403-701 cells/mm(3)). The prevalence of any and multiple HR-HPV infections was 83.4% and 60.5%, respectively. The most common types were HPV-16 (42%), HPV-51 (24%), HPV-39 (23.7%), and HPV-59 (23.5%). Age had a statistically significant, nonlinear association with the number of types, with the highest number detected around 35 years of age (P < .001). The number of recent sex partners had a statistically significant, fairly linear association on the log scale (P = .033). The high prevalence of HR-HPV types is associated with recent sexual behavior and age.
Subject(s)
Anal Canal/virology , HIV Infections/virology , Papillomaviridae/classification , Papillomavirus Infections/virology , Sexual Behavior , Adult , Age Factors , CD4 Lymphocyte Count , Coinfection/epidemiology , Coinfection/virology , DNA, Viral/analysis , DNA, Viral/genetics , Genotype , Genotyping Techniques , HIV/pathogenicity , HIV Infections/epidemiology , Human papillomavirus 16/classification , Human papillomavirus 16/genetics , Human papillomavirus 16/isolation & purification , Human papillomavirus 16/pathogenicity , Humans , Latin America/epidemiology , Male , Middle Aged , Papillomaviridae/genetics , Papillomaviridae/isolation & purification , Papillomaviridae/pathogenicity , Papillomavirus Infections/epidemiology , Poisson Distribution , Prevalence , Risk Factors , Sexual Partners , Spain/epidemiology , Viral LoadABSTRACT
The single-nucleotide polymorphism (SNP) rs12979860 near the IL28B gene has been associated with the spontaneous clearance of hepatitis C virus. We sought to determine whether this SNP could be associated with the spontaneous control of human immunodeficiency virus (HIV) infection. We studied the prevalence of the IL28B CC genotype among 53 white HIV controllers, compared with the prevalence among 389 HIV-infected noncontrollers. We found that the IL28B CC genotype was independently associated with spontaneous HIV control (odds ratio [OR], 2.669; P = .017), as were female sex (OR, 7.077; P ≤ .001) and the presence of HLA-B57 and/or B27 (OR, 3.080; P = .017). This result supports the idea that common host mechanisms are involved in the spontaneous control of these 2 chronic infections.
Subject(s)
HIV Infections/genetics , HIV Infections/immunology , Interleukins/genetics , Polymorphism, Single Nucleotide/genetics , White People/genetics , Adult , Female , Genotype , HIV Infections/virology , HLA-B Antigens/genetics , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/virology , Humans , Interferons , Male , Middle Aged , Viral LoadABSTRACT
BACKGROUNDWe evaluated the safety and viral rebound, after analytical treatment interruption (ATI), of vedolizumab and ART in recent HIV-1 infection. We used this model to analyze the effect of α4ß7 on the HIV-1 reservoir size.METHODSParticipants started ART with monthly vedolizumab infusions, and ATI was performed at week 24. Biopsies were obtained from ileum and cecum at baseline and week 24. Vedolizumab levels, HIV-1 reservoir, flow cytometry, and cell-sorting and antibody competition experiments were assayed.RESULTSVedolizumab was safe and well tolerated. No participant achieved undetectable viremia off ART 24 weeks after ATI. Only a modest effect on the time to achieve more than 1,000 HIV-1 RNA copies/mL and the proportion of participants off ART was observed, being higher in the vedolizumab group compared with historical controls. Just before ATI, α4ß7 expression was associated with HIV-1 DNA and RNA in peripheral blood and with PD1 and TIGIT levels. Importantly, a complete blocking of α4ß7 was observed on peripheral CD4+ T cells but not in gut (ileum and cecum), where α4ß7 blockade and vedolizumab levels were inversely associated with HIV-1 DNA.CONCLUSIONOur findings support α4ß7 as an important determinant in HIV-1 reservoir size, suggesting the complete α4ß7 blockade in tissue as a promising tool for HIV-cure combination strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT03577782.FUNDINGThis work was supported by the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, "a way to make Europe," research contracts FI17/00186 and FI19/00083 and research projects PI18/01532, PI19/01127, PI22/01796), Conserjería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía (research projects P20/00906), the Red Temática de Investigación Cooperativa en SIDA (RD16/0025/0020), and the Spanish National Research Council.