Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant

Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but... Open Forum Infectious Diseases MAJOR ARTICLE Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant 1,a 2 1 3 4 5 6 7 Juan Berenguer, Inmaculada Jarrín, Leire Pérez-Latorre, Víctor Hontañón, María J. Vivancos, Jordi Navarro, María J. Téllez, Josep M. Guardiola, 8 9 10 11 12 13 14 15 José A. Iribarren, Antonio Rivero-Juárez, Manuel Márquez, Arturo Artero, Luis Morano, Ignacio Santos, Javier Moreno, María C. Fariñas, 16 17 18 19 20 21 22 23 María J. Galindo, María A. Hernando, Marta Montero, Carmen Cifuentes, Pere Domingo, José Sanz, Lourdes Domíngez, Oscar L. Ferrero, 24 25 26 27 28 29 30 31 Belén De la Fuente, Carmen Rodríguez, Sergio Reus, José Hernández-Quero, Gabriel Gaspar, Laura Pérez-Martínez, Coral García, Lluis Force, 32 33 34 35 36 37 38 39 40 Sergio Veloso, Juan E. Losa, Josep Vilaró, Enrique Bernal, Sari Arponen, Amat J. Ortí, Ángel Chocarro, Ramón Teira, Gerardo Alonso, 41 42 43 44 45 3,a Rafael Silvariño, Ana Vegas, Paloma Geijo, Josep Bisbe, Herminia Esteban, and Juan González-García ; for the GeSIDA 8514 Study Group 1 2 3 Hospital General Universitario Gregorio Marañón/Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitario La 4 5 6 Paz/Instituto de Investigación Sanitaria La Paz, Madrid, Spain; Hospital Universitario Ramón y Cajal, Madrid, Spain; Hospital Vall d’Hebrón, Barcelona, Spain; Hospital Clínico de San Carlos, 7 8 9 Madrid, Spain; Hospital Santa Creu y San Pau, Barcelona, Spain; Hospital Universitario Donostia, San Sebastián, Spain; Hospital Universitario Reina Sofia/Instituto Maimónides de Investigación 10 11 12 13 Biomédica de Córdoba, Spain; Hospital Virgen de la Victoria, Málaga, Spain; Hospital Doctor Peset, Valencia, Spain; Hospital Universitario Álvaro Cunqueiro, Vigo, Spain; Hospital 14 15 16 Universitario de la Princesa, Madrid, Spain; Hospital Miguel Servet, Zaragoza, Spain; Hospital Universitario Marqués de Valdecilla, Santander, Spain; Hospital Clínico de Valencia, Spain; 17 18 19 20 Universidad Europea/Instituto de Investigación Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital La Fe, Valencia, Spain; Hospital Son Llátzer, Palma de Mallorca, Spain; Hospital 21 22 Universitario Arnau de Vilanova, Lleida, Spain; Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain; Hospital Universitario 12 de Octubre/ Instituto de Investigación Hospital 23 24 25 26 Universitario 12 de Octubre, Madrid, Spain; Universitario de Basurto, Bilbao, Spain; Hospital de Cabueñes, Gijón, Spain; Centro Sanitario Sandoval, Madrid, Spain; Hospital General de 27 28 29 30 Alicante, Spain; Hospital Clínico San Cecilio, Granada, Spain; Hospital Universitario de Getafe, Spain; Hospital de la Rioja, Logroño, Spain; Hospital Virgen de las Nieves, Granada, Spain; 31 32 33 34 35 36 Hospital de Mataró, Spain; Hospital Joan XXIII, Tarragona, Spain; Fundación Hospital Alcorcón, Spain; Hospital Universitari de Vic, Spain; Hospital Reina Sofía, Murcia, Spain; Hospital 37 38 39 Universitario de Torrejón, Torrejón de Ardoz, Spain; Hospital Virgen de la Cinta, Tortosa, Spain; Hospital Virgen de la Concha, Zamora, Spain; Hospital de Sierrallana, Torrelavega, Spain; 40 41 42 43 44 Hospital Rafael Méndez, Lorca, Spain; Hospital San Eloy, Baracaldo, Spain; Hospital Infanta Elena, Valdemoro, Spain; Hospital Virgen de la Luz, Cuenca, Spain; Fundació Hospital Sant Jaume, Olot, Spain; Fundación SEIMC-GESIDA, Madrid, Spain Background. We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies per - formed in 2002, 2009, and 2015. Methods. e s Th tudy was performed in 43 centers during October–November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-act- ing antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. Results. e r Th eference population and the sample size were 38 904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). e Th prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). e a Th nti-HCV treat- ment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV aer a ft nti-HCV therapy. Conclusions. Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the bur- den of HCV-related cirrhosis will continue to be significant among HIV-infected individuals. Keywords. coinfection/*epidemiology; hepatitis C/drug therapy/*epidemiology; HIV infection/*epidemiology; Spain/ epidemiology. Received 5 September 2017; editorial decision 16 November 2017; accepted 19 December 2017. J. B. and J. G.-G. contributed equally to this work. Coinfection by hepatitis C virus (HCV) is one of the most com- Correspondence: J. Berenguer, MD, PhD, Unidad de Enfermedades Infecciosas/VIH (4100), mon comorbidities in patients infected by the human immu- Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Doctor Esquerdo 46, 28007 Madrid, Spain (jbb4@me.com). nodeficiency virus (HIV), particularly in areas in which HIV Open Forum Infectious Diseases infection has been acquired mainly through injection drug use © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases (IDU) [1, 2]. However, since 2000, a substantial increase in the Society of America. This is an Open Access article distributed under the terms of the Creative number of new HCV infections has been reported among men Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any who have sex with men (MSM) involved in high-risk practices, medium, provided the original work is not altered or transformed in any way, and that the work particularly in metropolitan areas of Northern Europe, the is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofx258 United States of America, and Australia [3–5]. HIV/HCV Coinfection in Spain • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 In the last few years, the introduction of direct-acting anti- acid (RNA), whether patients were on combination antiretro- viral agents (DAAs) has revolutionized the treatment of HCV viral therapy (cART), and the regimen used. We also inquired [6] and has provided new opportunities for treatment of coin- about the presence of hepatitis B virus surface antigen (HBsAg), fected individuals, a population considered to be difficult to the presence of HCV antibodies, and—if applicable—the pres- treat in the interferon plus ribavirin era. ence of HCV-RNA. In patients with HCV antibodies, infor- In countries like Spain, where sexually acquired HCV infec- mation was also obtained about anti-HCV therapy and—if tion has contributed little to the burden of HIV/HCV coinfec- applicable—the regimens used and their outcomes. Patients tion to date, the prevalence of HCV antibodies and active HCV receiving anti-HCV therapy at the time the study was per- infection among HIV-infected individuals has decreased sub- formed were considered to be HCV-RNA positive. In the case stantially over the years owing to several factors, including the of patients with HCV antibodies and negative HCV-RNA, we decline in IDU as a mechanism of transmission of HIV infection, inquired whether this was due to spontaneous clearance or the greater mortality in HIV/HCV-coinfected patients than in to anti-HCV treatment. In patients with HCV antibodies and HIV-monoinfected patients, and the increased uptake of anti- who were HCV-RNA positive, we collected HCV genotype and HCV treatment [7, 8]. All these factors provide strong arguments subtype. In patients who were positive for HCV-RNA and/or in favor of actively monitoring the burden of HIV/HCV coinfec- HBsAg, transient elastography results and the date the proce- tion. In this study, we present data from a nationwide prevalence dure was performed were recorded. study of HIV/HCV coinfection in Spain carried out in 2016. e Th presence of liver cirrhosis was investigated in all patients, as was the method of diagnosis, namely, liver biopsy, transient SUBJECTS AND METHODS elastography (liver stiffness  >12.5 kPa), or clinical/biological findings. Patients with prior or current episodes of ascites, The study was carried out by “Grupo de Estudio del SIDA” hepatic encephalopathy, or variceal bleeding were considered (AIDS Study Group; GeSIDA) of the “Sociedad Española to have decompensated liver disease. In patients with cirrho- de Enfermedades Infecciosas y Microbiologıa Clınica” sis, current Child-Pugh and Model for End-Stage Liver Disease ([SEIMC] Spanish Society of Infectious Diseases and Clinical (MELD) scores were recorded. We also recorded whether Microbiology) between October 1, 2016 and December 30, patients had been diagnosed with hepatocellular carcinoma and 2016 after a methodology similar to that used in 3 previous whether they had undergone liver transplantation. We calcu- studies performed in 2002, 2009, and 2015 and reported in full lated anti-HCV treatment uptake, defined as the percentage of elsewhere [7, 9, 10]. patients with current or past chronic HCV infection exposed to Design and Sample Size Considerations anti-HCV therapy. This cross-sectional study was performed in 43 hospitals All the information was entered into a shared database at throughout Spain. The reference population was all HIV-infected each institution using an online electronic case report form. patients in active follow-up in the participating centers. Active A descriptive analysis was carried out using frequency tables for follow-up was defined as at least 1 visit to the center in the previ- categorical variables and mean and standard deviation (SD) or ous 12 months. Before the study was initiated, the total number of median and interquartile range (IQR) for normally and nonnor- patients in active follow-up at the participating centers was 38 904 mally distributed continuous variables. We used the χ test of and the prevalence of active HCV infection was 22.1%, accord- independence to detect significant differences in categorical var - ing to the most recent survey carried out by GeSIDA in 2015 [7]. iables and the t test or the nonparametric Mann-Whitney test for Based on these figures, a confidence level of 95%, a design effect differences in normally or nonnormally distributed continuous of 1.0, and an accuracy for the sample size of 2.0%, we estimated variables, respectively. All statistical analyses were performed that a sample of at least 1588 patients was needed. using Stata, version 14.0 (StataCorp, College Station, TX). Patient Selection The number of patients to be included at each center was deter- RESULTS mined by proportional allocation, and patients were selected by A total of 43 centers participated in the study. The reference simple random sampling (full details in [7]). The Institutional population was 38 904 HIV-infected patients, and the sample Ethics Committee of Hospital General Universitario Gregorio size was 1588 patients. Marañón approved the study and waived the requirement for writ- ten informed consent, because the study was based on anonym- Patients’ Characteristics ous routine clinical data intended for scientific publication. The characteristics of the 1588 patients included in the study are Variables and Statistical Analysis summarized in Table 1. No significant differences were found for We collected demographic data, HIV transmission category, sex between HCV-seronegative and HCV-seropositive patients; Centers for Diseases Control and Prevention (CDC) disease however, the latter were 4 years older than the former, on aver- category, current CD4 T-cell counts, current HIV-ribonucleic age. The frequency of IDU was significantly higher among 2 • OFID • Berenguer et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 HCV-seropositive patients than among HCV-seronegative prevalence of anti-HCV antibodies decreased significantly from patients, whereas the frequency of both transmission via het- 60.8% in 2002 to 37.7% in 2015 (P trend <.001) and remained erosexual relations and sexual relations between MSM was almost unchanged in 2016 (34.6%). In addition, the prevalence significantly higher among HCV-seronegative than among of active HCV infection decreased significantly from 54.0% in HCV-seropositive patients. Hepatitis B virus surface antigen 2002 to 11.7% in 2016 (P trend <.001). Of note, a 47.1% reduc- positivity was more frequent in HCV-seronegative patients than tion in the prevalence of active HCV infection was observed in HCV-seropositive patients (4.4% vs 2.5%; P < .019). from 2015 to 2016. In contrast, the decrease in the prevalence More HCV-seropositive patients were in CDC category C of active HCV infection was 37.0% in the 8-year period from than HCV-seronegative patients (30.3% vs 22.8%; P  <  .001). 2002 to 2009 and 35.0% in the 7-year period from 2009 to 2015. Overall, 96.7% of patients were on cART. In comparison with Anti-HCV treatment uptake in the 4 prevalence studies is HCV-seronegative patients, a small but significantly higher shown in Figure  3. e Th proportion of patients with current proportion of HCV-seropositive patients were on cART (98.2% or past chronic HCV infection exposed to anti-HCV therapy vs 95.8%, respectively; P  =  .014). In comparison with HCV- increased significantly from 23.0% in 2002 to 74.7% in 2016. seronegative patients, a significantly lower proportion of HCV- Characteristics of Patients With Active Hepatitis C Virus Infection seropositive patients were receiving a first-line cART regimen The characteristics of the 186 patients with active HCV infec- (22.9% vs 7.2%, respectively; P  <  .001). The proportion of tion are summarized in Table  3. A  total of 121 (65.1%) were patients with an HIV-RNA load <50 copies/mL was 89.5% over- naive for anti-HCV therapy, and 41 (22.0%) were receiving oral all and 92.2% in patients receiving cART. Among the latter, no DAA therapy during the study. Two patients (1.1%) with active significant differences were found between HCV-seropositive HCV infection had reinfections after sustained viral response and HCV-seronegative patients. In the full data set, statistically with pegylated interferon plus ribavirin. The HCV genotype significantly lower CD4 T-cell counts were found among HCV- was unknown in 10 patients (5.4%). Among the remaining seropositive patients than among HCV-seronegative patients 176 patients, the most common infecting genotypes were 1a (671 vs 654 cells/µL; P = .045) and in patients on cART (678 vs (46.6%), 4 (22.2%), 3 (15.9%), and 1b (13.6%). Transient elas- 659 cells/µL; P = .039), although the differences were small. tography was performed in 150 patients (80.6%) a median of Prevalence of Anti-Hepatitis C Virus (HCV) Antibodies and Active HCV 10 months before data were collected. The median liver stiffness Infection value was 6.6 kPa. The distribution of liver stiffness by cutoff Hepatitis C virus serostatus was known in 1585 (99.8%) patients, was as follows: <7.1 kPa (absent or mild liver fibrosis), 58.0%; 548 of whom were HCV seropositive. Of these 548 patients, 186 >9.5 kPa (advanced fibrosis), 23.3%; and >12.5 kPa (cirrhosis), were HCV-RNA positive, 292 were HCV-RNA negative after 16.0% [11]. In addition, the fibrosis-4 (FIB-4) score was avail- sustained viral response after anti-HCV therapy, 68 cleared able for 185 (99.5%) patients, 13.0% of whom had values ≥3.25 HCV spontaneously, and HCV-RNA results were unknown in 2.  (indicative of advanced liver fibrosis) [12]. The prevalence of anti-HCV antibodies was therefore 34.6% e m Th ain features of liver cirrhosis in patients with active HCV among tested patients (548 of 1585 patients whose serostatus infection and in those who cleared HCV infection aer a ft nti-HCV was known), and the prevalence of active HCV infection was therapy are summarized in Table 4. Liver cirrhosis was present in 11.7% (186 of 1583 patients with known HCV serostatus and 28 of 186 (15.0%) patients with active HCV infection and in 92 with known HCV-RNA among those with HCV antibodies). of 292 (31.5%) patients who cleared HCV aer a ft nti-HCV ther - apy. Thus, we can assume that of the 1588 HIV-infected patients Comparison With Previous Prevalence Studies included in the study, a diagnosis of HCV-related liver cirrhosis We compared the results of this study with those of 3 national had been made at some point in 120 (7.6%) patients. studies carried out by GeSIDA in 2002, 2009, and 2015 in a sim- ilar number of centers across the same geographical areas of DISCUSSION Spain [7, 9, 10]. A summary of participating centers, reference population, and sample size of the studies performed in 2002, This study showed that at the end of 2016, the prevalence of 2009, 2015, and 2016 is shown in Table 2. active HCV infection among HIV-infected individuals in Spain e Th main HIV transmission categories among HIV-infected was 11.7%. This represents an approximately 50% decrease individuals in the 4 prevalence studies are shown in Figure  1. in comparison with the prevalence found in 2015. This sharp From 2002 to 2015, there was a significant decrease in the pro- decrease occurred concurrently with increased access to oral portion of IDU (from 55.2% to 30.7%) and a significant increase DAAs for treatment of HCV. The study also showed that in the proportion of MSM (from 17.2% to 35.1%). However, no approximately 7.6% of all HIV-infected individuals in Spain significant changes were observed from 2015 to 2016. had HCV-related cirrhosis, a condition that was twice as com- e p Th revalence of anti-HCV antibodies and the prevalence of mon in coinfected patients with a sustained viral response than active HCV infection in the 4 studies are shown in Figure 2. The in those with active HCV infection. HIV/HCV Coinfection in Spain • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. Baseline characteristics of the 1588 Patients Included in the Study HCV Antibodies Unknown Positive Negative Total HCV-RNA HCV-RNA Negative HCV-RNA Negative Spontaneous HCV-RNA Total Positive Posttreatment Clearance Unknown HCV-Positive Characteristic n = 3 n = 186 n = 292 n = 68 n = 2 n = 548 n = 1037 P n = 1588 Male sex, n (%) 3 (100.0) 140 (75.3) 233 (79.8) 41 (60.3) 1 (50.0) 415 (75.7) 805 (77.6) .39 1223 (77.0) Age years, mean (SD) 51 (4) 50 (7) 52 (6) 51 (8) 50 (5) 51 (7) 47 (12) <.001 49 (11) HIV transmission category, n (%) Injection drug use 0 140 (75.3) 231 (79.1) 44 (64.7) 2 (100.0) 417 (76.1) 53 (5.1) <.001 470 (29.6) Heterosexual 0 22 (11.8) 22 (7.5) 14 (20.6) 0 58 (10.6) 318 (30.7) 376 (23.7) Men who have sex with 3 (100.0) 12 (6.4) 14 (4.8) 4 (5.9) 0 30 (5.5) 523 (50.4) 556 (35.0) men Contaminated blood 0 2 (1.1) 2 (0.7) 0 0 4 (0.7) 1 (0.1) 5 (0.3) products Mother-to-child 0 2 (1.1) 0 1 (1.5) 0 3 (0.5) 8 (0.8) 11 (0.7) transmission Other 0 8 (4.3) 23 (7.9) 5 (7.3) 0 36 (6.6) 134 (12.9) 170 (10.7) HBsAg, n (%) Negative 1 (33.3) 171 (91.9) 278 (95.2) 64 (94.1) 2 (100.0) 515 (94.0) 973 (93.8) .019 1489 (93.8) Positive 0 5 (2.7) 5 (1.7) 4 (5.9) 0 14 (2.5) 46 (4.4) 60 (3.8) Unknown 2 (66.7) 10 (5.4) 9 (3.1) 0 0 19 (3.5) 18 (1.7) 39 (2.5) CDC clinical category C, n 0 54 (29.0) 92 (31.5) 20 (29.4) 0 166 (30.3) 236 (22.8) .001 402 (25.3) (%) cART, n (%) 3 (100.0) 181 (97.3) 289 (99.0) 66 (97.1) 2 (100.0) 538 (98.2) 994 (95.8) .014 1535 (96.7) Type of cART regimen, n (%) 2 NRTI + 1 NNRTI 1 (33.3) 45 (24.9) 75 (25.9) 16 (24.2) 0 136 (25.2) 376 (37.8) <.001 513 (33.4) 2 NRTI + 1 PI 0 32 (17.7) 31 (10.7) 9 (13.6) 1 (50.0) 74 (13.7) 118 (11.9) 191 (12.4) 2 NRTI + 1 integrase 2 (66.7) 61 (33.7) 101 (34.9) 21 (31.8) 0 183 (33.9) 312 (31.4) 497 (32.4) inhibitor PI-based monotherapy 0 13 (7.2) 19 (6.6) 4 (6.1) 0 36 (6.7) 49 (4.9) 85 (5.5) PI-based bitherapy 0 15 (8.3) 30 (10.4) 8 (12.1) 0 53 (9.8) 56 (5.6) 109 (7.1) Other 0 15 (8.3) 33 (11.4) 8 (12.1) 1 (50.0) 57 (10.6) 83 (8.3) 140 (9.1) Category of cART regimen, n (%) First-line therapy 0 15 (8.3) 17 (5.9) 7 (10.6) 0 39 (7.2) 228 (22.9) <.001 267 (17.4) Switch unrelated to toxicity/ 1 (33.3) 100 (55.2) 168 (58.1) 28 (42.4) 1 (50.0) 298 (55.3) 436 (43.9) 734 (47.8) failure Switch after failure 0 24 (13.3) 19 (6.6) 8 (12.1) 1 (50.0) 52 (9.6) 60 (6.0) 112 (7.3) Switch after toxicity 2 (66.7) 40 (22.1) 80 (27.7) 22 (33.3) 0 142 (26.3) 240 (24.1) 384 (25.0) Unknown 0 2 (1.1) 5 (1.7) 1 (1.5) 0 8 (1.5) 30 (3.0) 38 (2.5) HIV-RNA copies/mL, n (%) All patients <50 3 (100.0) 158 (84.9) 276 (94.5) 57 (83.8) 2 (100.0) 493 (90.0) 926 (89.3) .15 1422 (89.5) 50–200 0 7 (3.8) 9 (3.1) 7 (10.3) 0 23 (4.2) 30 (2.9) 53 (3.3) >200 0 21 (11.3) 7 (2.4) 4 (5.9) 0 32 (5.8) 81 (7.8) 113 (7.1) Patients on cART <50 3 (100.0) 157 (86.7) 273 (94.5) 56 (84.8) 2 (100.0) 488 (90.7) 924 (93.0) .28 1415 (92.2) 50–200 0 7 (3.9) 9 (3.1) 7 (10.6) 0 23 (4.3) 30 (3.0) 53 (3.4) >200 0 17 (9.4) 7 (2.4) 3 (4.5) 0 27 (5.0) 40 (4.0) 67 (4.4) CD4 T cells/µL, median (IQR) All patients 744 (522–805) 600 (372–826) 680 (455–909) 764 (438–925) 205 (185–225) 654 (429–882) 671 (492–904) .045 670 (470–895) Patients on cART 744 (522–805) 605 (390–826) 684 (455–911) 764 (448–925) 205 (185–225) 659 (431–886) 678 (495–910) .039 670 (472–897) Abbreviations: cART, combination antiretroviral therapy; CDC, Centers for Disease Control and Prevention; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; HIV, human immu- nodeficiency virus; IQR, interquartile range; PI, protease inhibitor; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleoside reverse-transcriptase inhibitor; RNA, ribonucleic acid; SD, standard deviation. a 2 P values for the comparisons between HCV-positive patients (n = 548) and HCV-negative patients (n = 1037) derived from the χ test for independence for categorical variables and the t test or the Mann-Whitney test for normally or nonnormally distributed continuous variables, respectively. 4 • OFID • Berenguer et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Centers and Patients Included in the Nationwide HCV Prevalence the reduction of active HCV infection may be attributable to Studies Carried out by GeSIDA in 2002, 2009, 2015, and 2016 the increase in the frequency of anti-HCV treatment uptake, which went from 23.0% in 2002 to 59.3% and 74.7% in 2015 Variable 2002 2009 2015 2016 and 2016, respectively. Of note, in the last 2  years, anti-HCV Participating centers 39 43 41 43 therapy in Spain consisted of DAA-based regimens. Under real- Reference population 31 800 29 559 35 791 38 904 life conditions, these regimens yielded high rates of sustained Sample size 1260 1458 1867 1588 viral response that were similar to those of HCV-monoinfected Tested for HCV antibodies 99.5% 99.8% 98.7% 99.8% Reference 9 10 7 Current study patients and showed an excellent safety and tolerance profile, even in patients with end-stage liver disease [16, 17]. Abbreviations: GeSIDA, Grupo de Estudio del SIDA; HCV, hepatitis C virus; IQR, interquar- tile range; RNA, ribonucleic acid; TE, transient elastography. All of the above findings raise the question of whether the goal of elimination of HCV among HIV-infected individuals can be achieved in Spain in the short term. Elimination of an infec- e r Th esults of this study and previous GeSIDA studies [7 , 9, 10] tion means the reduction to zero of the incidence of the disease showed remarkable differences between the seroprevalence caused by a specific agent in a defined geographical area because of HCV and the prevalence of active HCV infection among of deliberate efforts, requiring continued measures to prevent HIV-infected individuals in the 14-year period from 2002 and re-establishment of transmission [18]. If one considers that pre- 2016. The seroprevalence of HCV dropped sharply from 2002 vention, screening, and universal access to treatment are essen- to 2015 but remained practically unchanged from 2015 to 2016 tial for the elimination of HCV infection [19], Spain appears to (approximately 35%). However, the prevalence of active HCV be on the right track towards the achievement of this goal. infection decreased steadily from 54.0% in 2002 to 11.7% in As previously mentioned, the preventive programs of the 2016. Of note, a 47% drop was observed from 2015 to 2016. This National Drug Strategy in Spain have proven effective for is a huge decrease if we consider that the decline in the preva- reduction of drug-related risk and harm [14]. These programs lence of active HCV infection was 37.0% in the 8-year period have included social and health services oer ff ing preventive from 2002 to 2009 and 35.0% in the 7-year period from 2009 to educational interventions, overdose prevention activities, ster- 2015, respectively. ile needles and syringes, testing for drug-related infections, vac- Several factors contributed to the declining trends in HCV cination against viral hepatitis, emergency care and assistance seropositivity and active infection among HIV-infected indi- to injecting drug users (who do not usually have contact with viduals from 2002 to 2016. In the early years, the main factor support interventions), and a scaling up of opioid substitution was the reduction in the frequency of IDU as a mechanism treatment. The National Drug Strategy for the period 2017–24 of HIV transmission [13], together with the development of covers many illicit and licit substances [14]. As this and previ- preventive drug programs [14]. The higher mortality rates in ous studies show, HCV infection acquired through sexual rela- coinfected patients compared with HIV-monoinfected patients tions contributes little to the burden of coinfection in Spain and in this period also contributed to a decrease in the preva- lence of HCV infection [15]. Over the last few years, however, HCV Ab+ *,** P trend < .001 HCV RNA+ ** *,** P trend < .001 IDU * * MSM ** ** ** ** ** ** 60.8 54.0 50.2 34.0 37.7 22.1 34.6 11.7 2002 2009 2015 2016 55.2 17.2 17.2 44.0 24.1 24.1 30.7 35.1 35.1 29.6 35.0 35.0 37.0% 35.0% 47.1% activ HCV infection activ HCV infection activ HCV infection 2002 2009 2015 2016 Year Year Figure  2. Prevalence of hepatitis C virus (HCV) seropositivity and active HCV Figure 1. Principal human immunodeficiency virus transmission categories in the infection in the cross-sectional studies carried out by Grupo de Estudio del SIDA in cross-sectional studies carried out by Grupo de Estudio del SIDA in 2002, 2009, 2002, 2009, 2015, and 2016. HCV Ab , presence of antibodies against HCV; HCV- 2015, and 2016. IDU, injection drug use; MSM, men who have sex with men. RNA , detectable HCV-RNA; RNA, ribonucleic acid. HIV/HCV Coinfection in Spain • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 % of patients % of patients Table 3. Characteristics of Liver Disease in the 186 Patients Who Were HCV-RNA Positive P trend < .001 Characteristic N = 186 Anti-HCV Therapy, n (%) Never 121 (65.1) Ongoing 41 (22.0) In the past 34 (18.3) Null response or partial response 26 (76.5) Relapse 1 (2.9) Abandonment or interruption due to adverse events 5 (14.7) 23.0% 48.0% 59.3% 74.7% Sustained viral response 2 (5.9) HCV Genotype, n (%) 2002 2009 2015 2016 Unknown 10 (5.4) Year Known 176 (94.6) 1 82 (46.6) 4 39 (22.2) Figure  3. Anti-hepatitis C virus (HCV) treatment uptake in the cross-sectional studies carried out by Grupo de Estudio del SIDA in 2002, 2009, 2015, and 2016. 1 24 (13.6) Treatment uptake was defined as the proportion of patients with current or past 3 28 (15.9) chronic HCV infection exposed to anti-HCV therapy 2 3 (1.7) Mixed 0 TE Results Patients with TE, n (%) 150 (80.6) remains restricted to specific areas of Madrid and Barcelona Months from TE to study date, median (IQR) 10.0 (5.6–21.9) [20, 21]. However, prevention activities should also be under- TE value–kPa, median (IQR) 6.6 (5.4–9.1) taken to reduce high-risk behavior among both HIV-infected TE distribution according to cutoff values–kPa, n (%) and non-HIV-infected MSM who engage in high-risk practices <7.1 87 (58.0) for sexual transmission of HCV [5]. 7.1–9.5 28 (18.7) Hepatitis C virus screening practices among HIV-infected 9.6–12.5 11 (7.3) >12.5 24 (16.0) individuals appear to be of a high standard according to the FIB-4 Index Results results of the 4 prevalence studies performed over the last Patients with FIB-4, n (%) 185 (99.5) 14  years, which have consistently shown that 99% of HIV- FIB-4 value, median (IQR) 1.5 (1.1–2.2) infected individuals are tested for HCV antibodies [7]. However, FIB-4 Distribution According to Cutoff Values, n (%) it is important to perform regular screening for HCV among ≤1 39 (21.1) 1–3.25 122 (65.9) HIV-infected people who engage in high-risk practices. In add- ≥3.25 24 (13.0) ition, testing should be considered in migrants from regions Abbreviations: DAA, direct-acting antiviral agent; FIB-4, fibrosis 4; HCV, hepatitis C virus; with a high prevalence of HCV, such as sub-Saharan Africa and IQR, interquartile range; RNA, ribonucleic acid; TE, transient elastography. Eastern Europe [22, 23]. The number of patients in the “never” , “ongoing” , and “in the past” categories total more than 186 because the groups overlap. Of the 186 patients, 121 were naive for anti-HCV As for universal access to therapy, a total of 63 075 patients therapy, 31 are currently receiving therapy but had not received it previously, 24 are not with HCV—20% of whom were coinfected—were treated with currently receiving therapy but had received it in the past, and 10 are currently receiving treatment and received it in the past. all oral DAA-based regimens in Spain from January 1, 2015 to All 41 patients in this category were receiving oral DAA therapy during the study. September 31, 2016 [24]. During the first months, access to therapy was prioritized for patients with advanced liver fibro- sis or cirrhosis; however, in 2015, in most autonomous regions An important observation in this study was the finding that of Spain, access to DAA therapy was available for patients with almost 8% of all HIV-infected individuals had been diagnosed significant fibrosis (METAVIR F ≥2 in liver biopsy or equivalent at some time with HCV-related liver cirrhosis. Of note, cir- by transient elastography). Furthermore, irrespective of liver rhosis was more common in patients who had achieved a sus- b fi rosis stage, DAA-based therapy could also be administered to tained viral response than in those with active HCV infection. patients with clinically significant extrahepatic manifestations This finding underscores the fact that despite the well known of HCV (such as symptomatic mixed cryoglobulinemia) and benefits of eradicating HCV among coinfected individuals in to patients at risk of transmitting HCV (active injection drug terms of reduced morbidity and mortality [26], there persists users, MSM with high-risk sexual practices for acquiring HCV, a residual risk for liver-related events, especially hepatocellular and women of childbearing age who wish to become pregnant). carcinoma, in patients with cirrhosis in whom HCV has been In June 2017, the Spanish Ministry of Health committed to eradicated [27, 28]. Therefore, even if we achieve the proba- providing access to DAA-based therapy for all individuals with ble and desired goal of eliminating HCV among HIV-infected HCV, irrespective of the stage of fibrosis [25]. individuals, the burden of HCV-related cirrhosis will remain 6 • OFID • Berenguer et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 % of patients Table 4. Features of Liver Cirrhosis in Patients With Active HCV Infection that the universal treatment of HCV and the continued efforts in and in Those Who Cleared HCV Infection After Anti-HCV Therapy prevention and screening will make it possible to eliminate active HCV infection among HIV-infected individuals in Spain in the Clearance of HCV short term. However, despite the elimination of active HCV infec- Active HCV After Infection Anti-HCV Therapy tion, HCV-related liver cirrhosis will continue to generate a signif- a icant burden among HIV-infected individuals in Spain. Feature N = 186 N = 292 P Liver cirrhosis, n (%) 28 (15.0) 92 (31.5) <.001 Acknowledgments Method of diagnosis (Mutually .30 We are grateful to Thomas O’Boyle for writing assistance during the Exclusive), n (%) preparation of the manuscript. Transient elastography 25 (89.3) 82 (89.1) Financial support. This work was funded by grant Ref. no. GLD14- Liver biopsy 0 5 (5.4) 00279 from the GILEAD Fellowship Programme (Spain) and by the Clinical/biological diagnosis 3 (10.7) 5 (5.4) Spanish AIDS Research Network (RD16/0025/0017, RD16/0025/0018) Decompensated cirrhosis, 4 (14.3) 8 (8.7) .39 that is included in the Spanish I+D+I Plan and is co-financed by ISCIII- n (%) Subdirección General de Evaluacion and European Funding for Regional Hepatocellular carcinoma, 1 (3.6) 1 (1.1) .37 Development (FEDER).  n (%) Potential coni fl cts of interest. J. B . is an investigator from the Programa Child-Pugh Stage, n (%) .13 de Intensificación de la Actividad Investigadora en el Sistema Nacional de Stage A (5–6) 22 (78.6) 80 (87.9) Salud (I3SNS) Ref. no. INT16/00100. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the edi- Stage B (7–9) 5 (17.9) 11 (12.1) tors consider relevant to the content of the manuscript have been disclosed. 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Open Forum Infectious Diseases MAJOR ARTICLE Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant 1,a 2 1 3 4 5 6 7 Juan Berenguer, Inmaculada Jarrín, Leire Pérez-Latorre, Víctor Hontañón, María J. Vivancos, Jordi Navarro, María J. Téllez, Josep M. Guardiola, 8 9 10 11 12 13 14 15 José A. Iribarren, Antonio Rivero-Juárez, Manuel Márquez, Arturo Artero, Luis Morano, Ignacio Santos, Javier Moreno, María C. Fariñas, 16 17 18 19 20 21 22 23 María J. Galindo, María A. Hernando, Marta Montero, Carmen Cifuentes, Pere Domingo, José Sanz, Lourdes Domíngez, Oscar L. Ferrero, 24 25 26 27 28 29 30 31 Belén De la Fuente, Carmen Rodríguez, Sergio Reus, José Hernández-Quero, Gabriel Gaspar, Laura Pérez-Martínez, Coral García, Lluis Force, 32 33 34 35 36 37 38 39 40 Sergio Veloso, Juan E. Losa, Josep Vilaró, Enrique Bernal, Sari Arponen, Amat J. Ortí, Ángel Chocarro, Ramón Teira, Gerardo Alonso, 41 42 43 44 45 3,a Rafael Silvariño, Ana Vegas, Paloma Geijo, Josep Bisbe, Herminia Esteban, and Juan González-García ; for the GeSIDA 8514 Study Group 1 2 3 Hospital General Universitario Gregorio Marañón/Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitario La 4 5 6 Paz/Instituto de Investigación Sanitaria La Paz, Madrid, Spain; Hospital Universitario Ramón y Cajal, Madrid, Spain; Hospital Vall d’Hebrón, Barcelona, Spain; Hospital Clínico de San Carlos, 7 8 9 Madrid, Spain; Hospital Santa Creu y San Pau, Barcelona, Spain; Hospital Universitario Donostia, San Sebastián, Spain; Hospital Universitario Reina Sofia/Instituto Maimónides de Investigación 10 11 12 13 Biomédica de Córdoba, Spain; Hospital Virgen de la Victoria, Málaga, Spain; Hospital Doctor Peset, Valencia, Spain; Hospital Universitario Álvaro Cunqueiro, Vigo, Spain; Hospital 14 15 16 Universitario de la Princesa, Madrid, Spain; Hospital Miguel Servet, Zaragoza, Spain; Hospital Universitario Marqués de Valdecilla, Santander, Spain; Hospital Clínico de Valencia, Spain; 17 18 19 20 Universidad Europea/Instituto de Investigación Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital La Fe, Valencia, Spain; Hospital Son Llátzer, Palma de Mallorca, Spain; Hospital 21 22 Universitario Arnau de Vilanova, Lleida, Spain; Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain; Hospital Universitario 12 de Octubre/ Instituto de Investigación Hospital 23 24 25 26 Universitario 12 de Octubre, Madrid, Spain; Universitario de Basurto, Bilbao, Spain; Hospital de Cabueñes, Gijón, Spain; Centro Sanitario Sandoval, Madrid, Spain; Hospital General de 27 28 29 30 Alicante, Spain; Hospital Clínico San Cecilio, Granada, Spain; Hospital Universitario de Getafe, Spain; Hospital de la Rioja, Logroño, Spain; Hospital Virgen de las Nieves, Granada, Spain; 31 32 33 34 35 36 Hospital de Mataró, Spain; Hospital Joan XXIII, Tarragona, Spain; Fundación Hospital Alcorcón, Spain; Hospital Universitari de Vic, Spain; Hospital Reina Sofía, Murcia, Spain; Hospital 37 38 39 Universitario de Torrejón, Torrejón de Ardoz, Spain; Hospital Virgen de la Cinta, Tortosa, Spain; Hospital Virgen de la Concha, Zamora, Spain; Hospital de Sierrallana, Torrelavega, Spain; 40 41 42 43 44 Hospital Rafael Méndez, Lorca, Spain; Hospital San Eloy, Baracaldo, Spain; Hospital Infanta Elena, Valdemoro, Spain; Hospital Virgen de la Luz, Cuenca, Spain; Fundació Hospital Sant Jaume, Olot, Spain; Fundación SEIMC-GESIDA, Madrid, Spain Background. We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies per - formed in 2002, 2009, and 2015. Methods. e s Th tudy was performed in 43 centers during October–November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-act- ing antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. Results. e r Th eference population and the sample size were 38 904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). e Th prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). e a Th nti-HCV treat- ment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV aer a ft nti-HCV therapy. Conclusions. Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the bur- den of HCV-related cirrhosis will continue to be significant among HIV-infected individuals. Keywords. coinfection/*epidemiology; hepatitis C/drug therapy/*epidemiology; HIV infection/*epidemiology; Spain/ epidemiology. Received 5 September 2017; editorial decision 16 November 2017; accepted 19 December 2017. J. B. and J. G.-G. contributed equally to this work. Coinfection by hepatitis C virus (HCV) is one of the most com- Correspondence: J. Berenguer, MD, PhD, Unidad de Enfermedades Infecciosas/VIH (4100), mon comorbidities in patients infected by the human immu- Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Doctor Esquerdo 46, 28007 Madrid, Spain (jbb4@me.com). nodeficiency virus (HIV), particularly in areas in which HIV Open Forum Infectious Diseases infection has been acquired mainly through injection drug use © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases (IDU) [1, 2]. However, since 2000, a substantial increase in the Society of America. This is an Open Access article distributed under the terms of the Creative number of new HCV infections has been reported among men Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any who have sex with men (MSM) involved in high-risk practices, medium, provided the original work is not altered or transformed in any way, and that the work particularly in metropolitan areas of Northern Europe, the is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofx258 United States of America, and Australia [3–5]. HIV/HCV Coinfection in Spain • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 In the last few years, the introduction of direct-acting anti- acid (RNA), whether patients were on combination antiretro- viral agents (DAAs) has revolutionized the treatment of HCV viral therapy (cART), and the regimen used. We also inquired [6] and has provided new opportunities for treatment of coin- about the presence of hepatitis B virus surface antigen (HBsAg), fected individuals, a population considered to be difficult to the presence of HCV antibodies, and—if applicable—the pres- treat in the interferon plus ribavirin era. ence of HCV-RNA. In patients with HCV antibodies, infor- In countries like Spain, where sexually acquired HCV infec- mation was also obtained about anti-HCV therapy and—if tion has contributed little to the burden of HIV/HCV coinfec- applicable—the regimens used and their outcomes. Patients tion to date, the prevalence of HCV antibodies and active HCV receiving anti-HCV therapy at the time the study was per- infection among HIV-infected individuals has decreased sub- formed were considered to be HCV-RNA positive. In the case stantially over the years owing to several factors, including the of patients with HCV antibodies and negative HCV-RNA, we decline in IDU as a mechanism of transmission of HIV infection, inquired whether this was due to spontaneous clearance or the greater mortality in HIV/HCV-coinfected patients than in to anti-HCV treatment. In patients with HCV antibodies and HIV-monoinfected patients, and the increased uptake of anti- who were HCV-RNA positive, we collected HCV genotype and HCV treatment [7, 8]. All these factors provide strong arguments subtype. In patients who were positive for HCV-RNA and/or in favor of actively monitoring the burden of HIV/HCV coinfec- HBsAg, transient elastography results and the date the proce- tion. In this study, we present data from a nationwide prevalence dure was performed were recorded. study of HIV/HCV coinfection in Spain carried out in 2016. e Th presence of liver cirrhosis was investigated in all patients, as was the method of diagnosis, namely, liver biopsy, transient SUBJECTS AND METHODS elastography (liver stiffness  >12.5 kPa), or clinical/biological findings. Patients with prior or current episodes of ascites, The study was carried out by “Grupo de Estudio del SIDA” hepatic encephalopathy, or variceal bleeding were considered (AIDS Study Group; GeSIDA) of the “Sociedad Española to have decompensated liver disease. In patients with cirrho- de Enfermedades Infecciosas y Microbiologıa Clınica” sis, current Child-Pugh and Model for End-Stage Liver Disease ([SEIMC] Spanish Society of Infectious Diseases and Clinical (MELD) scores were recorded. We also recorded whether Microbiology) between October 1, 2016 and December 30, patients had been diagnosed with hepatocellular carcinoma and 2016 after a methodology similar to that used in 3 previous whether they had undergone liver transplantation. We calcu- studies performed in 2002, 2009, and 2015 and reported in full lated anti-HCV treatment uptake, defined as the percentage of elsewhere [7, 9, 10]. patients with current or past chronic HCV infection exposed to Design and Sample Size Considerations anti-HCV therapy. This cross-sectional study was performed in 43 hospitals All the information was entered into a shared database at throughout Spain. The reference population was all HIV-infected each institution using an online electronic case report form. patients in active follow-up in the participating centers. Active A descriptive analysis was carried out using frequency tables for follow-up was defined as at least 1 visit to the center in the previ- categorical variables and mean and standard deviation (SD) or ous 12 months. Before the study was initiated, the total number of median and interquartile range (IQR) for normally and nonnor- patients in active follow-up at the participating centers was 38 904 mally distributed continuous variables. We used the χ test of and the prevalence of active HCV infection was 22.1%, accord- independence to detect significant differences in categorical var - ing to the most recent survey carried out by GeSIDA in 2015 [7]. iables and the t test or the nonparametric Mann-Whitney test for Based on these figures, a confidence level of 95%, a design effect differences in normally or nonnormally distributed continuous of 1.0, and an accuracy for the sample size of 2.0%, we estimated variables, respectively. All statistical analyses were performed that a sample of at least 1588 patients was needed. using Stata, version 14.0 (StataCorp, College Station, TX). Patient Selection The number of patients to be included at each center was deter- RESULTS mined by proportional allocation, and patients were selected by A total of 43 centers participated in the study. The reference simple random sampling (full details in [7]). The Institutional population was 38 904 HIV-infected patients, and the sample Ethics Committee of Hospital General Universitario Gregorio size was 1588 patients. Marañón approved the study and waived the requirement for writ- ten informed consent, because the study was based on anonym- Patients’ Characteristics ous routine clinical data intended for scientific publication. The characteristics of the 1588 patients included in the study are Variables and Statistical Analysis summarized in Table 1. No significant differences were found for We collected demographic data, HIV transmission category, sex between HCV-seronegative and HCV-seropositive patients; Centers for Diseases Control and Prevention (CDC) disease however, the latter were 4 years older than the former, on aver- category, current CD4 T-cell counts, current HIV-ribonucleic age. The frequency of IDU was significantly higher among 2 • OFID • Berenguer et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 HCV-seropositive patients than among HCV-seronegative prevalence of anti-HCV antibodies decreased significantly from patients, whereas the frequency of both transmission via het- 60.8% in 2002 to 37.7% in 2015 (P trend <.001) and remained erosexual relations and sexual relations between MSM was almost unchanged in 2016 (34.6%). In addition, the prevalence significantly higher among HCV-seronegative than among of active HCV infection decreased significantly from 54.0% in HCV-seropositive patients. Hepatitis B virus surface antigen 2002 to 11.7% in 2016 (P trend <.001). Of note, a 47.1% reduc- positivity was more frequent in HCV-seronegative patients than tion in the prevalence of active HCV infection was observed in HCV-seropositive patients (4.4% vs 2.5%; P < .019). from 2015 to 2016. In contrast, the decrease in the prevalence More HCV-seropositive patients were in CDC category C of active HCV infection was 37.0% in the 8-year period from than HCV-seronegative patients (30.3% vs 22.8%; P  <  .001). 2002 to 2009 and 35.0% in the 7-year period from 2009 to 2015. Overall, 96.7% of patients were on cART. In comparison with Anti-HCV treatment uptake in the 4 prevalence studies is HCV-seronegative patients, a small but significantly higher shown in Figure  3. e Th proportion of patients with current proportion of HCV-seropositive patients were on cART (98.2% or past chronic HCV infection exposed to anti-HCV therapy vs 95.8%, respectively; P  =  .014). In comparison with HCV- increased significantly from 23.0% in 2002 to 74.7% in 2016. seronegative patients, a significantly lower proportion of HCV- Characteristics of Patients With Active Hepatitis C Virus Infection seropositive patients were receiving a first-line cART regimen The characteristics of the 186 patients with active HCV infec- (22.9% vs 7.2%, respectively; P  <  .001). The proportion of tion are summarized in Table  3. A  total of 121 (65.1%) were patients with an HIV-RNA load <50 copies/mL was 89.5% over- naive for anti-HCV therapy, and 41 (22.0%) were receiving oral all and 92.2% in patients receiving cART. Among the latter, no DAA therapy during the study. Two patients (1.1%) with active significant differences were found between HCV-seropositive HCV infection had reinfections after sustained viral response and HCV-seronegative patients. In the full data set, statistically with pegylated interferon plus ribavirin. The HCV genotype significantly lower CD4 T-cell counts were found among HCV- was unknown in 10 patients (5.4%). Among the remaining seropositive patients than among HCV-seronegative patients 176 patients, the most common infecting genotypes were 1a (671 vs 654 cells/µL; P = .045) and in patients on cART (678 vs (46.6%), 4 (22.2%), 3 (15.9%), and 1b (13.6%). Transient elas- 659 cells/µL; P = .039), although the differences were small. tography was performed in 150 patients (80.6%) a median of Prevalence of Anti-Hepatitis C Virus (HCV) Antibodies and Active HCV 10 months before data were collected. The median liver stiffness Infection value was 6.6 kPa. The distribution of liver stiffness by cutoff Hepatitis C virus serostatus was known in 1585 (99.8%) patients, was as follows: <7.1 kPa (absent or mild liver fibrosis), 58.0%; 548 of whom were HCV seropositive. Of these 548 patients, 186 >9.5 kPa (advanced fibrosis), 23.3%; and >12.5 kPa (cirrhosis), were HCV-RNA positive, 292 were HCV-RNA negative after 16.0% [11]. In addition, the fibrosis-4 (FIB-4) score was avail- sustained viral response after anti-HCV therapy, 68 cleared able for 185 (99.5%) patients, 13.0% of whom had values ≥3.25 HCV spontaneously, and HCV-RNA results were unknown in 2.  (indicative of advanced liver fibrosis) [12]. The prevalence of anti-HCV antibodies was therefore 34.6% e m Th ain features of liver cirrhosis in patients with active HCV among tested patients (548 of 1585 patients whose serostatus infection and in those who cleared HCV infection aer a ft nti-HCV was known), and the prevalence of active HCV infection was therapy are summarized in Table 4. Liver cirrhosis was present in 11.7% (186 of 1583 patients with known HCV serostatus and 28 of 186 (15.0%) patients with active HCV infection and in 92 with known HCV-RNA among those with HCV antibodies). of 292 (31.5%) patients who cleared HCV aer a ft nti-HCV ther - apy. Thus, we can assume that of the 1588 HIV-infected patients Comparison With Previous Prevalence Studies included in the study, a diagnosis of HCV-related liver cirrhosis We compared the results of this study with those of 3 national had been made at some point in 120 (7.6%) patients. studies carried out by GeSIDA in 2002, 2009, and 2015 in a sim- ilar number of centers across the same geographical areas of DISCUSSION Spain [7, 9, 10]. A summary of participating centers, reference population, and sample size of the studies performed in 2002, This study showed that at the end of 2016, the prevalence of 2009, 2015, and 2016 is shown in Table 2. active HCV infection among HIV-infected individuals in Spain e Th main HIV transmission categories among HIV-infected was 11.7%. This represents an approximately 50% decrease individuals in the 4 prevalence studies are shown in Figure  1. in comparison with the prevalence found in 2015. This sharp From 2002 to 2015, there was a significant decrease in the pro- decrease occurred concurrently with increased access to oral portion of IDU (from 55.2% to 30.7%) and a significant increase DAAs for treatment of HCV. The study also showed that in the proportion of MSM (from 17.2% to 35.1%). However, no approximately 7.6% of all HIV-infected individuals in Spain significant changes were observed from 2015 to 2016. had HCV-related cirrhosis, a condition that was twice as com- e p Th revalence of anti-HCV antibodies and the prevalence of mon in coinfected patients with a sustained viral response than active HCV infection in the 4 studies are shown in Figure 2. The in those with active HCV infection. HIV/HCV Coinfection in Spain • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. Baseline characteristics of the 1588 Patients Included in the Study HCV Antibodies Unknown Positive Negative Total HCV-RNA HCV-RNA Negative HCV-RNA Negative Spontaneous HCV-RNA Total Positive Posttreatment Clearance Unknown HCV-Positive Characteristic n = 3 n = 186 n = 292 n = 68 n = 2 n = 548 n = 1037 P n = 1588 Male sex, n (%) 3 (100.0) 140 (75.3) 233 (79.8) 41 (60.3) 1 (50.0) 415 (75.7) 805 (77.6) .39 1223 (77.0) Age years, mean (SD) 51 (4) 50 (7) 52 (6) 51 (8) 50 (5) 51 (7) 47 (12) <.001 49 (11) HIV transmission category, n (%) Injection drug use 0 140 (75.3) 231 (79.1) 44 (64.7) 2 (100.0) 417 (76.1) 53 (5.1) <.001 470 (29.6) Heterosexual 0 22 (11.8) 22 (7.5) 14 (20.6) 0 58 (10.6) 318 (30.7) 376 (23.7) Men who have sex with 3 (100.0) 12 (6.4) 14 (4.8) 4 (5.9) 0 30 (5.5) 523 (50.4) 556 (35.0) men Contaminated blood 0 2 (1.1) 2 (0.7) 0 0 4 (0.7) 1 (0.1) 5 (0.3) products Mother-to-child 0 2 (1.1) 0 1 (1.5) 0 3 (0.5) 8 (0.8) 11 (0.7) transmission Other 0 8 (4.3) 23 (7.9) 5 (7.3) 0 36 (6.6) 134 (12.9) 170 (10.7) HBsAg, n (%) Negative 1 (33.3) 171 (91.9) 278 (95.2) 64 (94.1) 2 (100.0) 515 (94.0) 973 (93.8) .019 1489 (93.8) Positive 0 5 (2.7) 5 (1.7) 4 (5.9) 0 14 (2.5) 46 (4.4) 60 (3.8) Unknown 2 (66.7) 10 (5.4) 9 (3.1) 0 0 19 (3.5) 18 (1.7) 39 (2.5) CDC clinical category C, n 0 54 (29.0) 92 (31.5) 20 (29.4) 0 166 (30.3) 236 (22.8) .001 402 (25.3) (%) cART, n (%) 3 (100.0) 181 (97.3) 289 (99.0) 66 (97.1) 2 (100.0) 538 (98.2) 994 (95.8) .014 1535 (96.7) Type of cART regimen, n (%) 2 NRTI + 1 NNRTI 1 (33.3) 45 (24.9) 75 (25.9) 16 (24.2) 0 136 (25.2) 376 (37.8) <.001 513 (33.4) 2 NRTI + 1 PI 0 32 (17.7) 31 (10.7) 9 (13.6) 1 (50.0) 74 (13.7) 118 (11.9) 191 (12.4) 2 NRTI + 1 integrase 2 (66.7) 61 (33.7) 101 (34.9) 21 (31.8) 0 183 (33.9) 312 (31.4) 497 (32.4) inhibitor PI-based monotherapy 0 13 (7.2) 19 (6.6) 4 (6.1) 0 36 (6.7) 49 (4.9) 85 (5.5) PI-based bitherapy 0 15 (8.3) 30 (10.4) 8 (12.1) 0 53 (9.8) 56 (5.6) 109 (7.1) Other 0 15 (8.3) 33 (11.4) 8 (12.1) 1 (50.0) 57 (10.6) 83 (8.3) 140 (9.1) Category of cART regimen, n (%) First-line therapy 0 15 (8.3) 17 (5.9) 7 (10.6) 0 39 (7.2) 228 (22.9) <.001 267 (17.4) Switch unrelated to toxicity/ 1 (33.3) 100 (55.2) 168 (58.1) 28 (42.4) 1 (50.0) 298 (55.3) 436 (43.9) 734 (47.8) failure Switch after failure 0 24 (13.3) 19 (6.6) 8 (12.1) 1 (50.0) 52 (9.6) 60 (6.0) 112 (7.3) Switch after toxicity 2 (66.7) 40 (22.1) 80 (27.7) 22 (33.3) 0 142 (26.3) 240 (24.1) 384 (25.0) Unknown 0 2 (1.1) 5 (1.7) 1 (1.5) 0 8 (1.5) 30 (3.0) 38 (2.5) HIV-RNA copies/mL, n (%) All patients <50 3 (100.0) 158 (84.9) 276 (94.5) 57 (83.8) 2 (100.0) 493 (90.0) 926 (89.3) .15 1422 (89.5) 50–200 0 7 (3.8) 9 (3.1) 7 (10.3) 0 23 (4.2) 30 (2.9) 53 (3.3) >200 0 21 (11.3) 7 (2.4) 4 (5.9) 0 32 (5.8) 81 (7.8) 113 (7.1) Patients on cART <50 3 (100.0) 157 (86.7) 273 (94.5) 56 (84.8) 2 (100.0) 488 (90.7) 924 (93.0) .28 1415 (92.2) 50–200 0 7 (3.9) 9 (3.1) 7 (10.6) 0 23 (4.3) 30 (3.0) 53 (3.4) >200 0 17 (9.4) 7 (2.4) 3 (4.5) 0 27 (5.0) 40 (4.0) 67 (4.4) CD4 T cells/µL, median (IQR) All patients 744 (522–805) 600 (372–826) 680 (455–909) 764 (438–925) 205 (185–225) 654 (429–882) 671 (492–904) .045 670 (470–895) Patients on cART 744 (522–805) 605 (390–826) 684 (455–911) 764 (448–925) 205 (185–225) 659 (431–886) 678 (495–910) .039 670 (472–897) Abbreviations: cART, combination antiretroviral therapy; CDC, Centers for Disease Control and Prevention; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; HIV, human immu- nodeficiency virus; IQR, interquartile range; PI, protease inhibitor; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleoside reverse-transcriptase inhibitor; RNA, ribonucleic acid; SD, standard deviation. a 2 P values for the comparisons between HCV-positive patients (n = 548) and HCV-negative patients (n = 1037) derived from the χ test for independence for categorical variables and the t test or the Mann-Whitney test for normally or nonnormally distributed continuous variables, respectively. 4 • OFID • Berenguer et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Centers and Patients Included in the Nationwide HCV Prevalence the reduction of active HCV infection may be attributable to Studies Carried out by GeSIDA in 2002, 2009, 2015, and 2016 the increase in the frequency of anti-HCV treatment uptake, which went from 23.0% in 2002 to 59.3% and 74.7% in 2015 Variable 2002 2009 2015 2016 and 2016, respectively. Of note, in the last 2  years, anti-HCV Participating centers 39 43 41 43 therapy in Spain consisted of DAA-based regimens. Under real- Reference population 31 800 29 559 35 791 38 904 life conditions, these regimens yielded high rates of sustained Sample size 1260 1458 1867 1588 viral response that were similar to those of HCV-monoinfected Tested for HCV antibodies 99.5% 99.8% 98.7% 99.8% Reference 9 10 7 Current study patients and showed an excellent safety and tolerance profile, even in patients with end-stage liver disease [16, 17]. Abbreviations: GeSIDA, Grupo de Estudio del SIDA; HCV, hepatitis C virus; IQR, interquar- tile range; RNA, ribonucleic acid; TE, transient elastography. All of the above findings raise the question of whether the goal of elimination of HCV among HIV-infected individuals can be achieved in Spain in the short term. Elimination of an infec- e r Th esults of this study and previous GeSIDA studies [7 , 9, 10] tion means the reduction to zero of the incidence of the disease showed remarkable differences between the seroprevalence caused by a specific agent in a defined geographical area because of HCV and the prevalence of active HCV infection among of deliberate efforts, requiring continued measures to prevent HIV-infected individuals in the 14-year period from 2002 and re-establishment of transmission [18]. If one considers that pre- 2016. The seroprevalence of HCV dropped sharply from 2002 vention, screening, and universal access to treatment are essen- to 2015 but remained practically unchanged from 2015 to 2016 tial for the elimination of HCV infection [19], Spain appears to (approximately 35%). However, the prevalence of active HCV be on the right track towards the achievement of this goal. infection decreased steadily from 54.0% in 2002 to 11.7% in As previously mentioned, the preventive programs of the 2016. Of note, a 47% drop was observed from 2015 to 2016. This National Drug Strategy in Spain have proven effective for is a huge decrease if we consider that the decline in the preva- reduction of drug-related risk and harm [14]. These programs lence of active HCV infection was 37.0% in the 8-year period have included social and health services oer ff ing preventive from 2002 to 2009 and 35.0% in the 7-year period from 2009 to educational interventions, overdose prevention activities, ster- 2015, respectively. ile needles and syringes, testing for drug-related infections, vac- Several factors contributed to the declining trends in HCV cination against viral hepatitis, emergency care and assistance seropositivity and active infection among HIV-infected indi- to injecting drug users (who do not usually have contact with viduals from 2002 to 2016. In the early years, the main factor support interventions), and a scaling up of opioid substitution was the reduction in the frequency of IDU as a mechanism treatment. The National Drug Strategy for the period 2017–24 of HIV transmission [13], together with the development of covers many illicit and licit substances [14]. As this and previ- preventive drug programs [14]. The higher mortality rates in ous studies show, HCV infection acquired through sexual rela- coinfected patients compared with HIV-monoinfected patients tions contributes little to the burden of coinfection in Spain and in this period also contributed to a decrease in the preva- lence of HCV infection [15]. Over the last few years, however, HCV Ab+ *,** P trend < .001 HCV RNA+ ** *,** P trend < .001 IDU * * MSM ** ** ** ** ** ** 60.8 54.0 50.2 34.0 37.7 22.1 34.6 11.7 2002 2009 2015 2016 55.2 17.2 17.2 44.0 24.1 24.1 30.7 35.1 35.1 29.6 35.0 35.0 37.0% 35.0% 47.1% activ HCV infection activ HCV infection activ HCV infection 2002 2009 2015 2016 Year Year Figure  2. Prevalence of hepatitis C virus (HCV) seropositivity and active HCV Figure 1. Principal human immunodeficiency virus transmission categories in the infection in the cross-sectional studies carried out by Grupo de Estudio del SIDA in cross-sectional studies carried out by Grupo de Estudio del SIDA in 2002, 2009, 2002, 2009, 2015, and 2016. HCV Ab , presence of antibodies against HCV; HCV- 2015, and 2016. IDU, injection drug use; MSM, men who have sex with men. RNA , detectable HCV-RNA; RNA, ribonucleic acid. HIV/HCV Coinfection in Spain • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 % of patients % of patients Table 3. Characteristics of Liver Disease in the 186 Patients Who Were HCV-RNA Positive P trend < .001 Characteristic N = 186 Anti-HCV Therapy, n (%) Never 121 (65.1) Ongoing 41 (22.0) In the past 34 (18.3) Null response or partial response 26 (76.5) Relapse 1 (2.9) Abandonment or interruption due to adverse events 5 (14.7) 23.0% 48.0% 59.3% 74.7% Sustained viral response 2 (5.9) HCV Genotype, n (%) 2002 2009 2015 2016 Unknown 10 (5.4) Year Known 176 (94.6) 1 82 (46.6) 4 39 (22.2) Figure  3. Anti-hepatitis C virus (HCV) treatment uptake in the cross-sectional studies carried out by Grupo de Estudio del SIDA in 2002, 2009, 2015, and 2016. 1 24 (13.6) Treatment uptake was defined as the proportion of patients with current or past 3 28 (15.9) chronic HCV infection exposed to anti-HCV therapy 2 3 (1.7) Mixed 0 TE Results Patients with TE, n (%) 150 (80.6) remains restricted to specific areas of Madrid and Barcelona Months from TE to study date, median (IQR) 10.0 (5.6–21.9) [20, 21]. However, prevention activities should also be under- TE value–kPa, median (IQR) 6.6 (5.4–9.1) taken to reduce high-risk behavior among both HIV-infected TE distribution according to cutoff values–kPa, n (%) and non-HIV-infected MSM who engage in high-risk practices <7.1 87 (58.0) for sexual transmission of HCV [5]. 7.1–9.5 28 (18.7) Hepatitis C virus screening practices among HIV-infected 9.6–12.5 11 (7.3) >12.5 24 (16.0) individuals appear to be of a high standard according to the FIB-4 Index Results results of the 4 prevalence studies performed over the last Patients with FIB-4, n (%) 185 (99.5) 14  years, which have consistently shown that 99% of HIV- FIB-4 value, median (IQR) 1.5 (1.1–2.2) infected individuals are tested for HCV antibodies [7]. However, FIB-4 Distribution According to Cutoff Values, n (%) it is important to perform regular screening for HCV among ≤1 39 (21.1) 1–3.25 122 (65.9) HIV-infected people who engage in high-risk practices. In add- ≥3.25 24 (13.0) ition, testing should be considered in migrants from regions Abbreviations: DAA, direct-acting antiviral agent; FIB-4, fibrosis 4; HCV, hepatitis C virus; with a high prevalence of HCV, such as sub-Saharan Africa and IQR, interquartile range; RNA, ribonucleic acid; TE, transient elastography. Eastern Europe [22, 23]. The number of patients in the “never” , “ongoing” , and “in the past” categories total more than 186 because the groups overlap. Of the 186 patients, 121 were naive for anti-HCV As for universal access to therapy, a total of 63 075 patients therapy, 31 are currently receiving therapy but had not received it previously, 24 are not with HCV—20% of whom were coinfected—were treated with currently receiving therapy but had received it in the past, and 10 are currently receiving treatment and received it in the past. all oral DAA-based regimens in Spain from January 1, 2015 to All 41 patients in this category were receiving oral DAA therapy during the study. September 31, 2016 [24]. During the first months, access to therapy was prioritized for patients with advanced liver fibro- sis or cirrhosis; however, in 2015, in most autonomous regions An important observation in this study was the finding that of Spain, access to DAA therapy was available for patients with almost 8% of all HIV-infected individuals had been diagnosed significant fibrosis (METAVIR F ≥2 in liver biopsy or equivalent at some time with HCV-related liver cirrhosis. Of note, cir- by transient elastography). Furthermore, irrespective of liver rhosis was more common in patients who had achieved a sus- b fi rosis stage, DAA-based therapy could also be administered to tained viral response than in those with active HCV infection. patients with clinically significant extrahepatic manifestations This finding underscores the fact that despite the well known of HCV (such as symptomatic mixed cryoglobulinemia) and benefits of eradicating HCV among coinfected individuals in to patients at risk of transmitting HCV (active injection drug terms of reduced morbidity and mortality [26], there persists users, MSM with high-risk sexual practices for acquiring HCV, a residual risk for liver-related events, especially hepatocellular and women of childbearing age who wish to become pregnant). carcinoma, in patients with cirrhosis in whom HCV has been In June 2017, the Spanish Ministry of Health committed to eradicated [27, 28]. Therefore, even if we achieve the proba- providing access to DAA-based therapy for all individuals with ble and desired goal of eliminating HCV among HIV-infected HCV, irrespective of the stage of fibrosis [25]. individuals, the burden of HCV-related cirrhosis will remain 6 • OFID • Berenguer et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018 % of patients Table 4. Features of Liver Cirrhosis in Patients With Active HCV Infection that the universal treatment of HCV and the continued efforts in and in Those Who Cleared HCV Infection After Anti-HCV Therapy prevention and screening will make it possible to eliminate active HCV infection among HIV-infected individuals in Spain in the Clearance of HCV short term. However, despite the elimination of active HCV infec- Active HCV After Infection Anti-HCV Therapy tion, HCV-related liver cirrhosis will continue to generate a signif- a icant burden among HIV-infected individuals in Spain. Feature N = 186 N = 292 P Liver cirrhosis, n (%) 28 (15.0) 92 (31.5) <.001 Acknowledgments Method of diagnosis (Mutually .30 We are grateful to Thomas O’Boyle for writing assistance during the Exclusive), n (%) preparation of the manuscript. Transient elastography 25 (89.3) 82 (89.1) Financial support. This work was funded by grant Ref. no. GLD14- Liver biopsy 0 5 (5.4) 00279 from the GILEAD Fellowship Programme (Spain) and by the Clinical/biological diagnosis 3 (10.7) 5 (5.4) Spanish AIDS Research Network (RD16/0025/0017, RD16/0025/0018) Decompensated cirrhosis, 4 (14.3) 8 (8.7) .39 that is included in the Spanish I+D+I Plan and is co-financed by ISCIII- n (%) Subdirección General de Evaluacion and European Funding for Regional Hepatocellular carcinoma, 1 (3.6) 1 (1.1) .37 Development (FEDER).  n (%) Potential coni fl cts of interest. J. B . is an investigator from the Programa Child-Pugh Stage, n (%) .13 de Intensificación de la Actividad Investigadora en el Sistema Nacional de Stage A (5–6) 22 (78.6) 80 (87.9) Salud (I3SNS) Ref. no. INT16/00100. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the edi- Stage B (7–9) 5 (17.9) 11 (12.1) tors consider relevant to the content of the manuscript have been disclosed. 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Esteban. 8 • OFID • Berenguer et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx258/4804300 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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