Effectiveness of ritonavir-boosted protease inhibitor monotherapy in clinical practice even with previous virological failures to protease inhibitor-based regimens

López-Cortés, Luis F. et al.[Background and Objective] Significant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI)-based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens. [Methods] This retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure). [Results] A total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness (intention-to-treat analysis) and virological efficacy (on-treatment analysis) at week 96 were 79.3% (CI, 76.8-81.8) and 91.5% (CI, 89.6-93.4), respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations. [Conclusion] Switching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for the administered drug.All of the authors are members of the Sociedad Andaluza de Enfermedades Infecciosas (Andalusian Society of Infectious Diseases. http://www.saei.org/), which is the sponsor of this study.Peer Reviewe

No evidence of firstly acquired acute hepatitis C virus infection outbreak among HIV-infected patients from Southern Spain: a multicentric retrospective study from 2000-2014

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 HIVinfected 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.Plan Nacional R + D + I RD12/0017/0012ISCIII-Subdirección General de EvaluaciónFondo Europeo de Desarrollo Regional (FEDER) European Union (EU)Instituto de Salud Carlos III PI15/01124, CP13/00187, Programa-I3SN

High-resolution anoscopy in HIV-infected men: Assessment of the learning curve and factors that improve the performance

To determine the required learning time for high-resolution anoscopy (HRA)-guided biopsy to detect histological high-risk squamous intraepithelial lesions (hHSIL) and to identify factors that impact on the training process. Methods: All HIV-infected, screening-naïve men-who-have-sex-with-men who underwent HRA conducted by one single observer from 2010 to 2017 in a Spanish HIV-outpatient clinic were analysed. Results: Eighty-five (14.7%) of the 581 patients included presented hHSIL. The factors associated with the capacity to detect hHSIL [adjusted odds ratio (aOR), 95% confidence interval (95%CI)] were the presence of cytological HSIL (3.04, 1.78–5.21; p < 0.001), infection with high-risk human papilloma virus (HR-HPV) (2.89, 1.38–6.05; p=0.005), the number of biopsies taken/HRA (aOR: 1.28, 1.07–1.52; p=0.006) and tobacco smoking (1.75; 1.12–2.73; p=0.014). Two events independently augmented the detection rate of hHSIL: one single experienced pathologist interpreted biopsies after 409 HRA (2.80, 1.74–4.48; p=0.035) and the anoscopist underwent an additional training after 536 HRA (2.57, 1.07–6.16; p=0.035). A learning process could be observed throughout the whole study with stable HR-HPV prevalence. Conclusion: The data support the growing evidence that the proposed training volume of 50–200 performances is underestimated. Extensive training of both anoscopist and pathologist is warranted and the development of tools to support the diagnostic performance may be considered.Plan Nacional R+D+I y Red de Investigación en SIDA RD16/0025/0020-ISCIII-FEDMiguel Servet research grant, Instituto de Salud Carlos III CPII18/0003

Control of HIV-1 Pathogenesis in Viremic Nonprogressors Is Independent of Gag-Specific Cytotoxic T Lymphocyte Responses

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.We thank the founders for support of this project. We also thank all the centers and investigators involved in CoRIS. M.S. was supported by a Sara Borrell grant (CD11/00286). The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006 RD12/0017/0018, RD16/0025/0041) as part of the Plan Nacional R+D+I and cofinanced by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). This study was supported by the National Health Institute Carlos III (PI14/01058) and the Gilead Fellowship Program GLD 15/00298. J.G.P. holds a Miguel Servet II contract (CPII15/00014) funded by ISCIII. E.J.-M. is supported by Redes Temáticas de Investigación en SIDA (ISCIII RETIC RD16/0025/0041); Acción Estratégica en Salud; Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011; and Instituto de Salud Carlos III, Fondos FEDER. M.S., A.G.-M., and E.J.-M. performed the experiments. J.D., P.V., and B.A. selected and designed the cohorts. M.S., B.C., J.G.P., and J.M.-P. designed the experiments and drafted the paper. P.V. and B.A. are members of CoRISpe and the HIV HGM BioBank Study Group.S

Método de detección precoz de resistencias al tratamiento antirretroviral en VIH

Método de detección precoz de resistencias al tratamiento antirretroviral en VIH. La invención se refiere a una pareja de cebadores capaces de amplificar el gen pol del virus de inmunodeficiencia humana (VIH) a partir de muestras plasmáticas que contienen bajos niveles de carga viral (entre 10 y 1.000 copias de RNA viral/mL de plasma, más preferiblemente entre 20 y 1.000 copias/mL y aún más preferiblemente entre 20 y 100 copias/mL). Así, estos cebadores permiten la detección de VIH en muestras biológicas que presentan baja carga viral. El ARN del VIH así detectado se puede genotipar para, posteriormente, establecer un perfil de mutaciones de resistencia al tratamiento antirretroviral (TAR) en el VIH en pacientes que presentan una carga viral baja. Los métodos de la invención pueden, por tanto, ser empleados para la detección temprana de las mutaciones que en el VIH son responsables del fracaso del TAR incluso en los casos en los que los niveles de viremia en plasma son bajos, lo que permite modificar el tratamiento precozmente, evitar la aparición de nuevas mutaciones y proteger la eficacia de fármacos del régimen de tratamiento actual y de otros que puedan ser administrados en un futuro.Españ

Efficacy, safety and pharmacokinetic of once-daily boosted saquinavir (1500/100 mg) together with 2 nucleos(t)ide reverse transcriptase inhibitors in real life: a multicentre prospective study

<p>Abstract</p> <p>Background</p> <p>Ritonavir-boosted saquinavir (SQVr) is nowadays regarded as an alternative antiretroviral drug probably due to several drawbacks, such as its high pill burden, twice daily dosing and the requirement of 200 mg ritonavir when given at the current standard 1000/100 mg bid dosing. Several once-daily SQVr dosing schemes have been studied with the 200 mg SQV old formulations, trying to overcome some of these disadvantages. SQV 500 mg strength tablets became available at the end of 2005, thus facilitating a once-daily regimen with fewer pills, although there is very limited experience with this formulation yet.</p> <p>Methods</p> <p>Prospective, multicentre study in which efficacy, safety and pharmacokinetics of a regimen of once-daily SQVr 1500/100 mg plus 2 NRTIs were evaluated under routine clinical care conditions in either antiretroviral-naïve patients or in those with no previous history of antiretroviral treatments and/or genotypic resistance tests suggesting SQV resistance. Plasma SQV trough levels were measured by HPLV-UV.</p> <p>Results</p> <p>Five hundred and fourteen caucasian patients were included (47.2% coinfected with hepatitis C and/or B virus; 7.8% with cirrhosis). Efficacy at 52 weeks (plasma RNA-HIV <50 copies/ml) was 67.7% (CI₉₅: 63.6 - 71.7%) by intention-to-treat, and 92.2% (CI₉₅: 89.8 - 94.6%) by on-treatment analysis. The reasons for failure were: dropout or loss to follow-up (18.4%), virological failure (7.8%), adverse events (3.1%), and other reasons (4.6%). The high rate of dropout may be explained by an enrollement and follow-up under routine clinical care condition, and a population with a significant number of drug users. The median SQV Cmin (n = 49) was 295 ng/ml (range, 53-2172). The only variable associated with virological failure in the multivariate analysis was adherence (OR: 3.36; CI95, 1.51-7.46, p = 0.003).</p> <p>Conclusions</p> <p>Our results suggests that SQVr (1500/100 mg) once-daily plus 2 NRTIs is an effective regimen, without severe clinical adverse events or hepatotoxicity, scarce lipid changes, and no interactions with methadone. All these factors and its once-daily administration suggest this regimen as an appropriate option in patients with no SQV resistance-associated mutations.</p

Longitudinal study on adherence, treatment satisfaction, and effectiveness of once-daily versus twice-daily antiretroviral therapy in a Spanish cohort of HIV-infected patients (CUVA study)

INTRODUCCIÓN. La adherencia es esencial para el éxito del tratamiento antirretroviral (TAR), y la complejidad de la pauta es una barrera para el cumplimiento del TAR. La administración del TAR una vez al día (QD) reduce la complejidad al disminuir el número de tomas y potencialmente el de pastillas. El objetivo del estudio fue conocer el grado de adherencia y de satisfacción de los pacientes, en función de usar pautas QD frente a dos veces al día (BID), cuando la experiencia con QD era aún escasa. MÉTODOS. Estudio observacional, longitudinal y multicéntrico. Se incluyeron TAR de inicio (I), simplificaciones del TAR previo (S) y TAR de rescate (R). Se realizó visita inicial, y posteriormente a los 3 y 6 meses. Para evaluar la adherencia se utilizó un cuestionario previamente validado. La satisfacción con el TAR fue medida por personal independiente mediante una escala visual analógica (EVA). RESULTADOS. Se incluyeron un total de 978 pacientes (entre los meses de mayo y diciembre de 2002). La media de pastillas diarias fue de 5 QD frente a 6,1 BID. La carga vírica a los 6 meses fue indetectable en el 83,7% (I), el 87,5% (S) y el 57,4% (R), sin diferencias significativas entre QD y BID. La adherencia (el 61,4% QD frente al 53,2% BID; p < 0,05) y la satisfacción con el TAR (el 54,4% QD frente al 41,2% BID; p < 0,05) fueron significativamente mejores en las pautas QD. El análisis multivariable mostró como variables explicativas para: a) adherencia al TAR (odds ratio [OR]; intervalo de confianza [IC] del 95%): la satisfacción con el TAR (1,53; 1,30-1,80), apoyo familiar (1,25; 0,98-1,61), años de infección por el virus de la inmunodeficiencia humana (VIH) (0,97; 0,94-1,003) y la adicción intravenosa (0,83; 0,70-0,99); b) satisfacción con el TAR: grupo de simplificación (1,70; 1,22-2,34); pauta QD (1,33; 1,13-1,56); años de infección por el VIH (0,95; 0,93-0,98); estadio C (0,85; 0,73-1,01), y c) carga viral < 400 copias/ml: naïve (5,08; 3,14-8,22) y adherencia (1,57; 1,13-2,17). CONCLUSIÓN. Las pautas QD resultaron tan efectivas como las BID, mostrando una adherencia y satisfacción con el tratamiento significativamente mejores. Esto podría afectar positivamente la eficacia a largo plazo.Introduction: Adherence is essential for successful antiretroviral therapy (ART), but complex dosing schedules compromise the adherence to and efficacy of this treatment. Once-daily (QD) ART simplifies treatment by lowering the dosing frequency and pill burden. The aim of this study, performed when QD regimens were still limited, was to determine the degree of adherence and patient satisfaction of QD dosing versus twice-daily dosing (BID) of ART. Methods: Non-interventional, multicenter, longitudinal study, including initial (I), simplification (S), and rescue (R) therapies. Medical visits were performed at baseline, and at 3 and 6 months. A validated, structured questionnaire was used to assess adherence, and a visual analogical scale applied by independent observers was used to assess satisfaction. Results: From May to December 2002, 978 patients were recruited. Average pill burden was 5 in QD vs. 6.1 in BID regimens. Undetectable viral load was achieved at 6 months in 83.7% (I), 87.5% (S), and 57.4% (R) of patients, with no significant differences between QD and BID. Adherence and satisfaction with ART were both significantly better in QD vs. BID regimens: 61.4% vs. 53.2% (P < .05) and 54.4% vs. 41.2% (P < .05), respectively. Multivariate analysis revealed the following variables to account for 1) Adherence to ART (OR; 95% CI): treatment satisfaction (1.53, 1.30-1.80), family support (1.25, 0.98-1.61), years of HIV infection (0.97, 0.94-1.003) and intravenous drug use (0.83, 0.70-0.99); 2) Satisfaction with ART: simplification group (1.70, 1.22-2.34), QD therapy (1.33, 1.13-1.56), years of HIV infection (0.95, 0.93-0.98), and CDC stage C (0.85, 0.73-1.01); and 3) Undetectable viral load: naive group (5.08, 3.14-8.22) and adherence (1.57, 1.13-2.17). Conclusion: QD antiretroviral schedules appear to be as effective as BID regimens, with better adherence and treatment satisfaction. This may positively affect treatment efficacy at long-term

Effectiveness of the combination elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COB/TFV/FTC) plus darunavir among treatment-experienced patients in clinical practice: A multicentre cohort study

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) &lt; 50 copies/ml and &lt; 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (&lt; 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 &lt; 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL &lt; 50 copies/ml, 85.7% and 80.0% had VL &lt; 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL &lt; 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL &lt; 50 copies/ml and 69.2% and 68.2% had VL &lt; 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.The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional I + D + i and cofinanced by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER)”