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[Abstract] A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions. Ministerio de Economía y Empresa; IDI-20151125 Ministerio de Ciencia, Innovación y Universidades; SAF SAF 2017-87846-R

Since hepatitis C virus (HCV) and human T-lymphotropic virus (HTLV) share transmission routes, dual infection could be frequent. In Spain, HTLV underdiagnosis is highlighted by the high proportion of patients presenting either with tropical spastic paraparesis or adult T cell leukemia at first diagnosis. We examined whether the renewed efforts for expanding HCV testing may provide a sentinel population that might selectively be targeted to unveil asymptomatic HTLV carriers. The presence of anti-HTLV antibodies was examined in 3,838 consecutive individuals with reactive HCV serology attended during the last 3 years at 13 hospitals distributed across the Spanish geography. Overall 71% were male, and the median age was 41 years old. Foreigners represented 9% of the study population. A total of 50 individuals (1.3%) were seroreactive for HTLV, being 30 confirmed as HTLV-2 and 2 as HTLV-1 (0.12%). The remaining 18 had indeterminate Western blot patterns. Most individuals with HTLV-2 and HTLV indetermi...

Spanish HTLV Network., [Background] Human retroviruses HIV and HTLV share transmission routes. HIV widely spread in Spain during the 80 s through injection drug use and sex, and nowadays HIV rates in Spain account for one of the largest in Europe. In contrast, HTLV-1 is not endemic in Spain, despite hosting huge numbers of migrants from highly endemic regions. Herein, we report the rate and main features of the HIV-HTLV co-infected population in Spain., [Methods] A national registry exists in Spain for HTLV since year 1989. Data from standardized case report forms and one centralized lab repository were reviewed, especially for the subset with HTLV-HIV co-infection. [Results] Up to December 2018, a total of 369 individuals with HTLV-1 had been diagnosed in Spain. 64% of the population were females, and Latin American individuals accounted for 64.5%. Classical HTLV-associated illnesses were found in 12.7% (myelopathy) and 7.6% (leukemia). HIV coinfection was found in 12 (3.2%). Of those, 3 patients (25%) were female and 39 (75%) were of non-Spanish origin. All but two harbored HIV-1 subtype B, being non-B variants found in the two West Africans. Exposure had been sexual in most cases, being 4 homosexual men. Seven HTLV-HIV co-infected patients had developed AIDS and two had developed myelopathy. There was no evidence for increased HTLV-1 clinical pathogenicity due to HIV coinfection. [Conclusion] HIV coinfection is infrequent (

In Western Europe, the HIV-1 epidemic among men who have sex with men (MSM) is dominated by subtype B. However, recently, other genetic forms have been reported to circulate in this population, as evidenced by their grouping in clusters predominantly comprising European individuals. Here we describe four large HIV-1 non-subtype B clusters spreading among MSM in Spain. Samples were collected in 9 regions. A pol fragment was amplified from plasma RNA or blood-extracted DNA. Phylogenetic analyses were performed via maximum likelihood, including database sequences of the same genetic forms as the identified clusters. Times and locations of the most recent common ancestors (MRCA) of clusters were estimated with a Bayesian method. Five large non-subtype B clusters associated with MSM were identified. The largest one, of F1 subtype, was reported previously. The other four were of CRF02_AG (CRF02_1; n = 115) and subtypes A1 (A1_1; n = 66), F1 (F1_3; n = 36), and C (C_7; n = 17). Most individuals belonging to them had been diagnosed of HIV-1 infection in the last 10 years. Each cluster comprised viruses from 3 to 8 Spanish regions and also comprised or was related to viruses from other countries: CRF02_1 comprised a Japanese subcluster and viruses from 8 other countries from Western Europe, Asia, and South America; A1_1 comprised viruses from Portugal, United Kingom, and United States, and was related to the A1 strain circulating in Greece, Albania and Cyprus; F1_3 was related to viruses from Romania; and C_7 comprised viruses from Portugal and was related to a virus from Mozambique. A subcluster within CRF02_1 was associated with heterosexual transmission. Near full-length genomes of each cluster were of uniform genetic form. Times of MRCAs of CRF02_1, A1_1, F1_3, and C_7 were estimated around 1986, 1989, 2013, and 1983, respectively. MRCA locations for CRF02_1 and A1_1 were uncertain (however initial expansions in Spain in Madrid and Vigo, respectively, were estimated) and were most probable in Bilbao, Spain, for F1_3 and Portugal for C_7. These results show that the HIV-1 epidemic among MSM in Spain is becoming increasingly diverse through the expansion of diverse non-subtype B clusters, comprising or related to viruses circulating in other countries. This work was funded through Acción Estratégica en Salud Intramural (AESI), Instituto de Salud Carlos III, project “Estudios sobre vigilancia epidemiológica molecular del VIH-1 en España,” PI16CIII/00033; Red de Investigación en SIDA (RIS), Instituto de Salud Carlos III, Subdirección General de Evaluación y Fondo Europeo de Desarrollo Regional (FEDER), Plan Nacional I+D+I, project RD16ISCIII/0002/0004; scientific agreements with Consellería de Sanidade, Government of Galicia (MVI 1004/16) and Osakidetza-Servicio Vasco de Salud, Government of Basque Country (MVI 1001/16); European Research Infrastructures for Poverty Related Diseases (EURIPRED). Seventh Framework Program: FP7-Capacities-infrastructures-2012-1, grant agreement 312661; and Dirección General de Farmacia, Ministerio de Sanidad, Servicios Sociales e Igualdad, Government of Spain (grant EC11-272). Sí

Human T-lymphotropic virus type 1 (HTLV-1) infection is a neglected disease despite roughly 15 million people are chronically infected worldwide. Lifelong less than 10% of carriers develop life-threatening diseases, mostly a subacute myelopathy known as tropical spastic paraparesis (TSP) and a lymphoproliferative disorder named adult T-cell leukemia (ATL). HTLV-1 is efficiently transmitted perinatally (breastfeeding), sexually (more from men to women) and parenterally (transfusions, injection drug user (IDU), and transplants). To date there is neither prophylactic vaccine nor effective antiviral therapy. A total of 327 cases of HTLV-1 infection had been reported at the HTLV-1 Spanish registry until December 2016, of whom 34 had been diagnosed with TSP and 25 with ATL. Overall 62% were Latin American immigrants and 13% were persons of African origin. The incidence of HTLV-1 in Spain has remained stable for nearly a decade with 20–25 new cases yearly. Of the 21 newly diagnosed HTLV-1 cases during year 2016, one was a native Spaniard pregnant woman, and four presented with symptomatic disease, including three with ATL and one with TSP. Underdiagnosis of HTLV-1 in Spain must be high (iceberg model), which may account for the disproportionate high rate of symptomatic cases (almost 20%) and the late recognition of preventable HTLV-1 transmissions in special populations, such as newborns and transplant recipients. Our current estimate is of 10 000 persons living with HTLV-1 infection in Spain. Given the large flux of immigrants and visitors from HTLV-1 endemic regions to Spain, the expansion of HTLV-1 screening policies is warranted. At this time, it seems worth recommending HTLV testing to all donor/recipient organ transplants and pregnant women regardless place of birth. Although current leukoreduction procedures largely prevent HTLV-1 transmission by blood transfusions, HTLV testing of all first-time donors should be cost-effective contributing to unveil asymptomatic unaware HTLV-1 carriers., The work was funded in part by grants from F-IES and ISCIII-Fondos Feder (PI13/01574; ICI14/00372; CD14/0243; FI14/0264; CM13/0309; CES12/003).