Estudio de efectividad, tolerancia y predictores de evolución desfavorable del tratamiento del virus de la Hepatitis C con agentes antivirales directos en una cohorte multicéntrica de pacientes con infección por VIH

Estudio de cohorte prospectivo, multicéntrico, de pacientes coinfectados por VIH /VHC procedentes de 9 centros sanitarios en la región de Castilla la Mancha tratados con agentes antivirales directos (AADs) de segunda generación. Se incluyeron todos los pacientes con ARN del VHC sérico detectable naïves a AADs de segunda generación (se incluyeron aquellos que habían fracasado a terapias con boceprevir y/o telaprevir). Nuestros objetivos fueron: evaluar la eficacia y la seguridad de los AADs y compararla con datos procedentes de ensayos clínicos y estudios observacionales; identificar los factores asociados al fracaso terapéutico y analizar la evolución de la fibrosis y los factores asociados a una disminución de la rigidez hepática medida por elastografía. Recogimos variables demográficas, biológicas, analíticas y elastográficas basales y en visitas sucesivas. La elastografía hepática se realizó mediante FibroScan®. El objetivo primario fue la evaluación de la respuesta viral sostenida (RVS) en la semana 12 después de finalizar el tratamiento. Se realizaron análisis por intención de tratar (AIT) y por datos observados (ADO). Se utilizaron modelos bivariables y multivariables para ajustar los efectos de los factores de confusión. Los modelos se desarrollaron a partir de variables significativas del análisis bivariable (p <0,005) y otras consideradas relevantes en la literatura. Para el análisis estadístico utilizados los paquetes SPSS 12.0 y Stata 15.0. Entre el 15 de julio de 2014 y el 1 de abril de 2018, 316 pacientes comenzaron el tratamiento con AADs de segunda generación. La mayoría eran hombres (82,1%), con una mediana de edad de 50,3 años (RIC: 46,9-53,3) y ex usuarios de fármacos parenterales (75,5%). El 43.9% presentaba criterios de cirrosis hepática. Un 30.3% admitía un consumo de alcohol en cantidades perjudiciales. El 40,6% había fracasado a tratamientos previos. La combinación más utilizada fue sofosbuvir + ledipasvir (35.2%), seguida de ombitasvir / paritaprevir / ritonavir + dasabuvir (19.1%), sofosbuvir + daclastasvir (16.4%) y sofosbuvir + simeprevir (14.4%). Un 44,5% también utilizó ribavirina. La duración de las pautas fue de 12 (64.5%), 24 (25.5%) y 8 (8,2%) semanas. En el AIT, se logró la RVS en el 90.9% (IC95%: 87.3-93.6) sin diferencias entre los centros. En el ADO, se excluyeron aquellos pacientes que interrumpieron el tratamiento y no alcanzaron la RVS, y los fallecimientos y pérdidas de seguimiento ocurridos entre las fechas de final del tratamiento y RVS. Se alcanzó la curación en 298 sujetos (93.7%; IC95%: 90.5-95.6). En el AIT, 30 pacientes no lograron la RVS (4 interrupciones prematuras del tratamiento, 4 pérdidas de seguimiento, 4 muertes y 18 fallos virológicos). De los pacientes cirróticos, el 89% (IC95%: 8.9-94.1) en el AIT y el 94.1% (IC95%: 90.1-98.1) en el ADO alcanzaron la RVS, sin hallar diferencias con aquellos sin cirrosis. Después de ajustar por otras variables, sólo el consumo de alcohol (OR: 0,33; IC95%: 0,138-0,789, p=0,013) y las cifras basales mayores de bilirrubina (OR: 0,595; IC95%: 0,416-0,851, p=0.004) se asociaron significativamente al fracaso terapéutico. Analizamos la evolución de la fibrosis hepática a lo largo del tiempo en 178 pacientes de los que disponíamos al menos 2 elastografías. La mediana de seguimiento fue de 16,3 meses (RIC: 12,5-24,9). La mediana de disminución de la rigidez hepática fue de 2,6 kPas (0-6.3). El 52,8% experimentó una disminución suficiente como para ser clasificado en una categoría inferior en la escala de Metavir. El análisis multivariable mostró una fuerte asociación entre la RVS y la regresión de la fibrosis (OR: 17.369; IC95%: 1.833-164.625; p=0.013). El evento clínico adverso grave más frecuente fue la descompensación hepática que se produjo en 10 pacientes (3%), conllevando la muerte en 4 casos. Ocho pacientes interrumpieron el tratamiento por efectos adversos relacionados con la medicación. El principal efecto adverso clínico fue la fatiga (5,1%). La anemia fue el hallazgo analítico adverso más observado (3,9%). Nuestro estudio confirma la extraordinaria eficacia y seguridad de los AADs de segunda generación en sujetos coinfectados con VIH descrita en los ensayos clínicos. El abuso del alcohol se asoció a una menor eficacia, si bien podría estar asociado a una menor adherencia. La evaluación de la fibrosis durante el seguimiento mostró resultados prometedores que podrían traducirse en una mejora de la inflamación, pero también en la cura real de las células hepáticas

Effectiveness and tolerability of dolutegravir/lamivudine for the treatment of HIV-1 infection in clinical practice

Objectives: To assess the effectiveness and tolerability of dolutegravir (DTG)/lamivudine (3TC) among treatment-naive and virologically suppressed treatment-experienced individuals in the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) during the years 2018-2021. Methods: We used multivariable regression models to compare viral suppression (VS) [HIV RNA viral load (VL) <50 copies/mL] and the change in CD4 cell counts at 24 and 48 (±12) weeks after initiation with dolutegravir/lamivudine or other first-line ART regimens. Results: We included 2160 treatment-naive subjects, among whom 401 (18.6%) started with dolutegravir/lamivudine. The remaining subjects started bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (n = 949, 43.9%), DTG + FTC/tenofovir disoproxil fumarate (TDF) (n = 282, 13.1%), DTG/3TC/abacavir (ABC) (n = 255, 11.8%), darunavir (DRV)/cobicistat(COBI)/FTC/TAF (n = 147, 6.8%) and elvitegravir (EVG)/COBI/FTC/TAF (n = 126, 5.8%). At 24 and 48 weeks after starting dolutegravir/lamivudine, 91.4% and 93.8% of the subjects, respectively, achieved VS. The probability of achieving VS with dolutegravir/lamivudine was not significantly different compared with any other regimen at 24 or 48 weeks, with the exception of a lower chance of achieving VS at 24 weeks for DRV/COBI/FTC/TAF (adjusted OR: 0.47; 95% CI: 0.30-0.74) compared with dolutegravir/lamivudine.For the analysis of treatment-experienced virally suppressed subjects we included 1456 individuals who switched to dolutegravir/lamivudine, among whom 97.4% and 95.5% maintained VS at 24 and 48 weeks, respectively. During the first 48 weeks after dolutegravir/lamivudine initiation, 1.0% of treatment-naive and 1.5% of treatment-experienced subjects discontinued dolutegravir/lamivudine due to an adverse event. Conclusions: In this large multicentre cohort, effectiveness and tolerability of dolutegravir/lamivudine were high among treatment-naive and treatment-experienced subjects.This work was supported by (i) 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 co-financed by Instituto de Salud Carlos III-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), and (ii) ViiV Healthcare. The funders did not play any decision making role in the design, execution, analysis or reporting of the research.S

Cross neutralization of SARS‐CoV‐2 omicron subvariants after repeated doses of COVID‐19 mRNA vaccines

We have measured the humoral response to messenger RNA (mRNA) vaccines in COVID-19 naïve and convalescent individuals. Third doses of mRNA COVID-19 vaccines induced a significant increase in potency and breadth of neutralization against SARS-CoV-2 variants of concern (VoC) including Omicron subvariants BA.1, BA.2, and BA.2.12.1, that were cross-neutralized at comparable levels and less for BA.4/5. This booster effect was especially important in naïve individuals that only after the third dose achieved a level that was comparable with that of vaccinated COVID-19 convalescents except for BA.4/5. Avidity of RBD-binding antibodies was also significantly increased in naïve individuals after the third dose, indicating an association between affinity maturation and cross neutralization of VoC. These results suggest that at least three antigenic stimuli by infection or vaccination with ancestral SARS-CoV-2 sequences are required to induce high avidity cross-neutralizing antibodies. Nevertheless, the circulation of new subvariants such as BA.4/5 with partial resistance to neutralization will have to be closely monitored and eventually consider for future vaccine developments

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Actualización en el tratamiento de la coinfección por VIH y VHC en pacientes adultos

El presente artículo es una revisión sobre el tratamiento del VHC en pacientes infectados por el VIH. Se aborda brevemente el contexto epidemiológico, la interacción existente entre ambos virus, y la historia natural e inmunopatogenia del VHC. Posteriormente se analizan las estrategias históricas (que incluían el interferón pegilado) y las actuales con los nuevos agentes antivirales directos. Se profundiza en las indicaciones, el concepto de respuesta viral sostenida, la eficacia, la toxicidad, y el tratamiento en situaciones especiales como la infección aguda por VHC o el trasplante hepático. Por último, se aborda la evolución de la fibrosis hepática, el trasplante hepático, el riesgo de hepatocarcinoma y el impacto poblacional de la curación de la infección por VHC.This article is a review of the treatment of HCV in HIV-infected patients. The epidemiological context, the interaction between both viruses, and the natural history and immunopathogenesis of HCV are briefly addressed. Subsequently, the historical strategies (including pegylated interferon) and the current ones with the new direct antiviral agents are analyzed. The indications, the concept of sustained viral response, efficacy, toxicity, and treatment in special situations such as acute HCV infection or liver transplantation are deepened. Finally, the progress of liver fibrosis, hepatic transplantation, the risk of hepatocellular carcinoma and population impact of curing HCV infection is discussed

Long-term efficacy of dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: Week 96 results of ART-PRO pilot study

Background: In the ART-PRO pilot trial there were no virological failures through 48 weeks of treatment with dolutegravir plus lamivudine in suppressed individuals with and without archived lamivudine resistance-associated mutations (RAMs) detected through next-generation sequencing (NGS) but without evidence of lamivudine RAMs in baseline proviral DNA population sequencing. Objectives: To present 96 week results from ART-PRO. Methods: Open-label, single-arm pilot trial. At baseline, all participants switched to dolutegravir plus lamivudine. Participants were excluded if proviral DNA population genotyping detected lamivudine RAMs. To detect resistance minority variants, proviral DNA NGS was retrospectively performed from baseline samples. For this analysis the efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 96. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. Results: Forty-one participants were included, 21 with lamivudine RAMs in historical plasma RNA genotypes. Baseline proviral DNA NGS detected lamivudine RAMs (M184V/I and/or K65R/E/N) above a 5% threshold in 71.4% (15/21) and 15% (3/20) of participants with and without history of lamivudine resistance, respectively. At 96 weeks, 90.2% of participants achieved the efficacy endpoint. Between week 48 and 96 there was one discontinuation due to consent withdrawal and no discontinuations related to adverse events. Two participants had a transient viral rebound, both re-suppressed on dolutegravir plus lamivudine. Through week 96, there were no virological failures. Conclusions: In this pilot trial, dolutegravir plus lamivudine maintained virological suppression at 96 weeks despite historical lamivudine resistance and persisting archived minority lamivudine RAMs.Instituto de Salud Carlos III (PI16/00837 -PI16/00678)Rio Hortega fellowship from Fondo de Investigaciones Sanitarias (CM17/00064)Instituto de Salud Carlos III European Commission (JR15/00031)PFIS fellowship from Fondo de Investigaciones Sanitarias (FI17/00194; CM19/00059)5.790 JCR (2020) Q1, 43/276 Pharmacology & Pharmacy2.124 SJR (2020) Q1, 27/292 Infecticus DiseasesNo data IDR 2020UE

Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO)

Background We investigated the efficacy of a switch to dolutegravir plus lamivudine in aviremic individuals without evidence of persistent lamivudine resistance-associated mutations in baseline proviral DNA population sequencing. Methods Open-label, single-arm, 48-week pilot trial. HIV-1 infected adults, naïve to integrase inhibitors, with CD4+ above 350 cell/μL and fewer than 50 HIV-1 RNA copies per mL the year prior to study entry switched to dolutegravir plus lamivudine. Participants were excluded if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. To detect resistance minority variants, proviral DNA next-generation sequencing was retrospectively performed from baseline samples. Primary efficacy endpoint was proportion of participants with fewer than 50 HIV-1 RNA copies per mL at week 48. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. ART-PRO is registered with ClinicalTrials.gov, NCT03539224. Findings 41 participants switched to dolutegravir plus lamivudine, 21 with lamivudine resistance mutations in historical plasma genotypes. Baseline next-generation sequencing detected lamivudine resistance mutations (M184V/I and/or K65R/E/N) over a 5% threshold in 15/21 (71·4%) and 3/20 (15%) of participants with and without history of lamivudine resistance, respectively. At week 48, 92·7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine. There were 28 drug-related adverse events, only one leading to discontinuation. Interpretation In this pilot trial, dolutegravir plus lamivudine was effective in maintaining virologic control despite past historical lamivudine resistance and presence of archived lamivudine resistance-associated mutations detected by next generation sequencing. Further studies are needed to confirm our results.Instituto de Salud Carlos III PI16/00837-PI16/006788.143 JCR (2020) Q1, 17/140 Medicine, Research & Experimental2.596 SJR (2020) Q1, 23/254 Biochemistry, Genetics and Molecular Biology (miscellaneous)No data IDR 2020UE

Use of Tenofovir Alafenamide/Emtricitabine/Elvitegravir-Cobicistat in HIV-Naive Patients with Advanced Disease: GENIS Study.

Objective: The primary endpoint of the study was to determine the proportion of patients with HIV RN

Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO).

We investigated the efficacy of a switch to dolutegravir plus lamivudine in aviremic individuals without evidence of persistent lamivudine resistance-associated mutations in baseline proviral DNA population sequencing. Open-label, single-arm, 48-week pilot trial. HIV-1 infected adults, naïve to integrase inhibitors, with CD4+ above 350 cell/μL and fewer than 50 HIV-1 RNA copies per mL the year prior to study entry switched to dolutegravir plus lamivudine. Participants were excluded if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. To detect resistance minority variants, proviral DNA next-generation sequencing was retrospectively performed from baseline samples. Primary efficacy endpoint was proportion of participants with fewer than 50 HIV-1 RNA copies per mL at week 48. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. ART-PRO is registered with ClinicalTrials.gov, NCT03539224. 41 participants switched to dolutegravir plus lamivudine, 21 with lamivudine resistance mutations in historical plasma genotypes. Baseline next-generation sequencing detected lamivudine resistance mutations (M184V/I and/or K65R/E/N) over a 5% threshold in 15/21 (71·4%) and 3/20 (15%) of participants with and without history of lamivudine resistance, respectively. At week 48, 92·7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine. There were 28 drug-related adverse events, only one leading to discontinuation. In this pilot trial, dolutegravir plus lamivudine was effective in maintaining virologic control despite past historical lamivudine resistance and presence of archived lamivudine resistance-associated mutations detected by next generation sequencing. Further studies are needed to confirm our results. Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III PI16/00837-PI16/00678.Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III PI16/00837-PI16/00678.S

Efectividad del tratamiento con agentes antivirales directos en pacientes con coinfección por VHC y VIH. Estudio de cohorte multicéntrico

RESUMEN Introducción: la eficacia de los agentes antivirales directos (AAD) ha quedado demostrada en ensayos clínicos tanto en mono como en coinfectados. Nuestro objetivo es analizar la efectividad y toxicidad de este tratamiento en vida real en pacientes con coinfección por VIH y VHC así como determinar variables asociadas a una evolución desfavorable. Métodos: estudio ambispectivo multicéntrico en una cohorte de pacientes coinfectados. Los datos fueron recogidos en ocho centros de Castilla-La Mancha entre 2014 y 2016. Se realizó un análisis por intención de tratamiento en el que cualquier pérdida de seguimiento, abandono de tratamiento o toxicidad terapéutica se consideró fracaso. Resultados: se estudiaron 229 pacientes con una mediana de edad de 49,6 años con predominio masculino (83%). Menos de un 10% presentaba carga viral (CV) detectable para el VIH. El genotipo de VHC más prevalente fue el 1 (65,1%). Un 50% tenía hepatopatía en grado de cirrosis. El 65% presentaba más de 800.000 copias/ml de CV de VHC. La respuesta viral sostenida (RVS) se alcanzó globalmente en el 91,7%. La estrategia de AAD más utilizada fue sofosbuvir/ledipasvir. Un 52% de las pautas incluyeron ribavirina. El 65,9% completó pautas de 12 semanas y un 30%, de 24 semanas. Hubo 19 fracasos terapéuticos. No existen diferencias entre las distintas estrategias de AAD utilizadas. No se observó ningún factor predictor independiente de RVS. Conclusiones: el tratamiento del VHC en pacientes coinfectados presenta tasas de RVS muy elevadas también en vida real. La toxicidad es excepcional. No hemos identificado factores predictores específicos de evolución desfavorable