Received: 1 October 2021 | Accepted: 23 December 2021 DOI: 10.1111/hiv.13229 ORIGINAL RESEARCH Epidemiological trends of HIV/HCV coinfection in Spain, 2015–­2019 Chiara Fanciulli1,2 | Juan Berenguer1,2,† | Carmen Busca2,3 | María J. Vivancos2,4 | María J. Téllez2,5 | Lourdes Domínguez2,6 | Pere Domingo7 | Jordi Navarro2,8 | Jesús Santos9 | José A. Iribarren10 | Luis Morano11 | Arturo Artero12 | Javier Moreno13 | Antonio Rivero-­Román2,14 | Ignacio Santos2,15 | Livia Giner16 | Carlos Armiñanzas2,17 | Marta Montero18 | Christian Manzardo19,20 | Carmen Cifuentes21 | Coral García22 | María J. Galindo23 | Oscar L. Ferrero24 | José Sanz25 | Belén de la Fuente26 | Carmen Rodríguez27 | Gabriel Gaspar28 | Laura Pérez29 | Juan E. Losa30 | Luis Force31 | Sergio Veloso32 | Elisa Martínez-­Alfaro33 | Inmaculada Jarrín2,34 | Marta De Miguel35 | Juan González Garcia2,3,† | GeSIDA 8514 Study Group 1 Infectious Diseases and Clinical Microbiology, Hospital General Universitario Gregorio Marañón (IiSGM), Madrid, Spain 2 Unit of Infectious Diseases, Hospital Universitario Reina Sofia. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba (UCO), Cordoba, Spain 3 HIV Unit, Internal Medicine, Hospital Universitario La Paz (IdiPAZ), Madrid, Spain 4 Infectious Diseases, Hospital Ramón y Cajal (Irycis), Madrid, Spain 5 Infectious Diseases, Hospital Clínico San Carlos, Madrid, Spain 6 HIV Unit, Internal Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain 7 Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 8 Infectious Diseases, Hospital Universitari Vall d´Hebrón, Barcelona, Spain 9 Infectious Diseases, Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain 10 Infectious Diseases, Hospital Donostia, San Sebastián, Spain 11 Infectious Diseases, Hospital Universitario Álvaro Cunqueiro, Vigo, Spain 12 Internal Medicine and Infectious Diseases, Hospital Universitario Doctor Peset, Valencia, Spain 13 Infectious Diseases, Hospital Universitario Miguel Servet, Zaragoza, Spain 14 CIBERINFEC, Madrid, Spain 15 Infectious Diseases, Hospital Universitario de la Princesa, Madrid, Spain 16 Infectious Diseases, Hospital General Universitario de Alicante, Alicante, Spain 17 Infectious Diseases, Hospital Universitario Marqués de Valdecilla, Santander, Spain 18 Infectious Diseases, Hospital Universitario y Politécnico La Fe, Valencia, Spain 19 Infectious Diseases, Hospital Arnau de Vilanova, Lleida, Spain 20 Infectious Diseases, Hospital Santa María, Lleida, Spain † These authors contributed equally to this work. The members of the ‘GeSIDA 8514 Study Group’ are given in Appendix section. [Correction added on 21 March 2022, after first online publication: the affiliations of Antonio Rivero-Román have been corrected in this version.] This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association. HIV Medicine. 2022;23:705–716. wileyonlinelibrary.com/journal/hiv   | 705 |    14681293, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13229 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 706 FANCIULLI et al. 21 Infectious Diseases, Hospital Son Llàtzer, Palma de Mallorca, Mallorca, Spain 22 Infectious Diseases, Hospital Universitario Virgen de las Nieves, Granada, Spain 23 Internal Medicine and Infectious Diseases, Hospital Clínico de Valencia, Valencia, Spain 24 Infectious Diseases, Hospital Universitario de Basurto, Bilbao, Spain 25 Infectious Diseases, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain 26 Infectious Diseases, Hospital Universitario de Cabueñes, Gijón, Spain 27 Centro Sanitario Sandoval, Madrid, Spain 28 Internal Medicine and Infectious Diseases, Hospital Universitario de Getafe, Getafe, Spain 29 Infectious Diseases, Hospital San Pedro, Logroño, Spain 30 Infectious Diseases, Fundación Hospital Alcorcón, Alcorcón, Spain 31 Internal Medicine and Infectious Diseases, Hospital de Mataró, Mataró, Spain 32 Infectious Diseases, Hospital Universitario Joan XXIII, Tarragona, Spain 33 Infectious Diseases, Complejo Hospitalario Universitario de Albacete, Albacete, Spain 34 Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain 35 Fundación SEIMC/GeSIDA, Madrid, Spain Correspondence Juan Berenguer, Unidad de Abstract Enfermedades Infecciosas/VIH Objectives: We assessed the prevalence of anti-­hepatitis C virus (HCV) anti- (4100), Hospital General Universitario bodies and active HCV infection (HCV-­RNA-­positive) in people living with HIV Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio (PLWH) in Spain in 2019 and compared the results with those of four similar Marañón (IiSGM), Doctor Esquerdo 46, studies performed during 2015–­2018. 28007 Madrid, Spain. Email: jbb4@me.com Methods: The study was performed in 41 centres. Sample size was estimated for an accuracy of 1%. Patients were selected by random sampling with proportional Funding information allocation. This work was supported in part by the Spanish AIDS Research Network Results: The reference population comprised 41 973 PLWH, and the sample (RD16/0025/0017, RD16/0025/0018), size was 1325. HCV serostatus was known in 1316 PLWH (99.3%), of whom 376 which is included in the Spanish I+D+I (28.6%) were HCV antibody (Ab)-­positive (78.7% were prior injection drug users); Plan and is co-­funded by the ISCIII-­ Subdirección General de Evaluación 29 were HCV-­RNA-­positive (2.2%). Of the 29 HCV-­RNA-­positive PLWH, infec- and European Funding for Regional tion was chronic in 24, it was acute/recent in one, and it was of unknown du- Development (FEDER). The sponsors ration in four. Cirrhosis was present in 71 (5.4%) PLWH overall, three (10.3%) had no role in the study design, the collection, analysis and interpretation HCV-­RNA-­positive patients and 68 (23.4%) of those who cleared HCV after anti-­ of data, the writing of the report, or HCV therapy (p = 0.04). The prevalence of anti-­HCV antibodies decreased stead- the decision to submit the article for publication. ily from 37.7% in 2015 to 28.6% in 2019 (p < 0.001); the prevalence of active HCV infection decreased from 22.1% in 2015 to 2.2% in 2019 (p < 0.001). Uptake of anti-­HCV treatment increased from 53.9% in 2015 to 95.0% in 2019 (p < 0.001). Conclusions: In Spain, the prevalence of active HCV infection among PLWH at the end of 2019 was 2.2%, i.e. 90.0% lower than in 2015. Increased exposure to DAAs was probably the main reason for this sharp reduction. Despite the high coverage of treatment with direct-­acting antiviral agents, HCV-­related cirrhosis remains significant in this population. KEYWORDS coinfection/*epidemiology, hepatitis C/drug therapy/*epidemiology, HIV infection/*epidemiology I N T RO DU CT ION mainly through injection drug use (IDU) [1] or sexual practices with a high risk of mucosal transmission in the Coinfection by hepatitis C virus (HCV) is a common com- case of men who have sex with men (MSM) [2]. HIV in- plication in people living with HIV (PLWH) acquired fection modifies the natural history of HCV, increasing | 14681293, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13229 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HIV MEDICINE     707 chronic infection rates [3], accelerating liver fibrosis [4] informed consent, as it was based on anonymous, routine and hastening progression to end-­stage liver disease [5]. clinical data intended for scientific publication. However, the harmful effect of HIV infection on the nat- ural history of hepatitis C can be mitigated with effective ART [6]. Study design and sample size estimation The introduction of direct-­acting antiviral agents (DAAs) against HCV has revolutionized the treatment of The study was performed in 41 hospitals throughout Spain hepatitis C, particularly among HIV/HCV-­coinfected pa- following a methodology similar to that used in four previ- tients and those with decompensated cirrhosis, both of ous studies performed yearly from 2015 to 2018 [18–­21]. which are groups that were considered difficult to treat The reference population consisted solely of PLWH in in the interferon + ribavirin era [7]. The benefits of HCV active follow-­up in the participating centres, defined as clearance following anti-­HCV therapy in coinfected peo- at least one visit to the centre in the previous 12 months. ple include a reduction in liver-­related complications and Before the study was initiated, the total number of PLWH mortality [8], a decrease in HIV progression and morbid- in active follow-­up at the participating centres was 41 973, ity and mortality not related to liver disease [9], and a re- and the prevalence of active HCV infection according to duced risk of transmission of HCV [10]. the most recent survey carried out by GeSIDA in 2018 was The epidemiology of HIV/HCV coinfection is poorly 3.7% [22]. Based on these figures, we estimated that a sam- known in many European countries and is subject to vari- ple of at least 1325 PLWH was needed for a confidence ability depending on testing and changes in the factors that level of 95%, a design effect of 1.0, and an accuracy for the determine the transmission of each virus [11]. Of great sample size of 1.0%. The PLWH were selected by simple significance has been the decrease in IDU as a mechanism random sampling with proportional allocation. fuelling the HIV and HCV epidemics in some countries, including Spain [12], and the greater mortality associated with HIV/HCV coinfection than with HIV monoinfection Investigations [13]. In addition, the lack of protective immunity against HCV favours reinfection after viral clearance when prac- The sources of data were the medical records. We collected tices with a high risk of transmission are maintained [14]. demographics, HIV transmission category, Centers for This phenomenon is even more concerning because of the Diseases Control and Prevention (CDC) disease category, growing number of HCV infections among HIV-­negative current CD4 T-­cell counts, current HIV-­RNA load, whether MSM on pre-­exposure prophylaxis against HIV [15] who PLWH were on ART, and the ART regimen used. We also engage in transmission networks involving HIV-­infected enquired about the presence of hepatitis B virus surface MSM [16]. One mitigating factor is the scale-­up of DAA antigen (HBsAg), the presence of HCV antibodies, and treatment, which can decrease the population HCV bur- –­ if applicable –­ HCV-­RNA. Those PLWH receiving anti-­ den and, consequently, the risk of new HCV infections HCV therapy at the time the study was performed were despite ongoing high-­risk transmission practices [17]. All considered to be HCV-­RNA-­positive. In PLWH who were these factors provide solid arguments for active monitor- HCV-­RNA-­positive, information was requested regarding ing of the burden of HIV/HCV coinfection. the time since diagnosis of HCV infection (< 12 months Here, we present data from a nationwide study of the or ≥ 12 months) and HCV genotype and subtype. In PLWH prevalence of HIV/HCV coinfection in Spain in 2019 and with HCV antibodies, information was also obtained about compare the results with those of four similar studies per- prior anti-­HCV therapy and, if applicable, the regimens formed during 2015–­2018. used and their outcomes. In PLWH with active HCV in- fection who were not receiving anti-­HCV therapy, the reasons for not receiving treatment were requested. In PAT I E NT S A N D M ET H ODS PLWH with HCV antibodies and negative HCV-­RNA, we queried whether this was due to spontaneous clearance or The study was carried out by AIDS Study Group [‘Grupo anti-­HCV treatment. In PLWH who were positive for HCV-­ de Estudio del SIDA’ (GeSIDA) of the Spanish Society of RNA or HBsAg, transient elastography results and the date Infectious Diseases and Clinical Microbiology (‘Sociedad the procedure was performed were recorded. Española de Enfermedades Infecciosas y Microbiología Cirrhosis was investigated in all PLWH, as was the Clínica’ (SEIMC)] between 1 October 2019 and 30 method of diagnosis, namely, liver biopsy, transient November 2019. The Institutional Ethics Committee of elastography (liver stiffness > 12.5 kPa) or clinical/bi- Hospital General Universitario Gregorio Marañón ap- ological findings. The Fibrosis-­4 (FIB-­4) score was also proved the study and waived the requirement for written calculated, and values ≥ 3.25 were considered indicative |    14681293, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13229 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 708 FANCIULLI et al. of advanced liver fibrosis/cirrhosis. In PLWH with cir- PLWH. HBsAg positivity was more frequent in HCV-­ rhosis, current Child-­Pugh and model for end-­stage seropositive PLWH than in HCV-­seronegative PLWH liver disease (MELD) scores were recorded. We calcu- (4.3% vs. 2.3%; p = 0.036). lated anti-­HCV treatment uptake, defined as the per- More HCV-­seropositive than HCV-­seronegative PLWH centage of PLWH with current infection or past chronic were in CDC category C (25.0% vs 18.3%; p = 0.015). HCV infection exposed to anti-­HCV therapy. All the Overall, 98.0% were on ART, with a small but statistically information was recorded at each institution using an significant difference between HCV-­seronegative and online electronic case report form. HCV-­seropositive patients (98.5% vs. 96.8%; p = 0.024). Compared with HCV-­seronegative PLWH, a lower propor- tion of HCV-­seropositive PLWH were on a first-­line ART Statistics regimen (17.6% vs. 4.9%, respectively; p < 0.001). Significant differences were also found between HCV-­seronegative and A descriptive analysis was carried out using frequency HCV-­seropositive PLWH in the distribution of ART regi- tables for categorical variables and mean and standard mens, with a higher frequency of integrase strand transfer deviation (SD) or median and interquartile range (IQR), inhibitors and nonnucleoside reverse transcriptase inhibi- respectively, for normally and non-­normally distributed tors as the anchor drugs among the former (p = 0.03). The continuous variables. We used the χ2 test of independence proportion of PLWH with an HIV-­RNA load < 50 copies/ to detect significant differences in categorical variables mL was 91.5% overall and 92.6% in those receiving ART, and the t-­test or Mann–­Whitney test for differences in nor- with no significant differences in this regard between HCV-­ mally or non-­normally distributed continuous variables, seropositive and HCV-­seronegative PLWH. Statistically respectively. All statistical analyses were performed using significantly lower CD4 T-­cell counts were found among Stata (v.14.0; StataCorp). HCV-­seropositive PLWH than among HCV-­seronegative PLWH overall (643 vs. 707 cells/µL; p < 0.001) and in those on ART (640 vs. 710 cells/µL; p < 0.001). RES ULT S A total of 41 centres participated in the study. The refer- Characteristics of liver disease in HIV/ ence population consisted of 41 973 PLWH, and the sam- HCV-­coinfected PLWH ple size was 1325 PLWH. The characteristics of liver disease in the 29 PLWH with active HCV infection identified in 2019 are shown in Prevalence of HIV/HCV coinfection Table S1. None were considered to have HCV reinfection. The infection had occurred within the previous 12 months In the 2019 prevalence study, HCV serostatus was known in only one out of 25 with a known date of diagnosis. in 1316 of 1325 PLWH (99.3%), 376 of whom were Eleven of the 29 PLWH with active HCV infection (37.9%) HCV-­seropositive. Of these 376 PLWH, 29 were HCV-­ received oral DAA therapy during the study period but RNA-­positive, 291 were HCV-­RNA-­negative following were considered infected by definition, and four (13.8%) anti-­HCV therapy, and 55 cleared HCV spontaneously; were due to initiate treatment. The main reasons for not HCV-­RNA results were unknown in one. Therefore, the being on or having programmed therapy were physician prevalence of anti-­HCV antibodies was 28.6% [95% con- decision (N = 5), unknown (N = 4), loss to follow-­up fidence interval (CI): 26.1–­31.1%], and the prevalence of (N = 3) and patient refusal (N = 2). Liver cirrhosis was pre- active HCV infection was 2.2% (1.5–­3.1%). sent in three out of 29 (10.3%) PLWH with active HCV in- fection, all with compensated liver disease, and in 68 out of 291 (23.4%) PLWH who cleared HCV following anti-­HCV Characteristics of PLWH therapy. The main features of liver cirrhosis in PLWH with active HCV infection and those who cleared HCV infec- The characteristics of the PLWH included in the 2019 sero- tion following anti-­HCV therapy are shown in Table S2. prevalence study are summarized in Table 1. No significant differences were found for sex between HCV-­seronegative PLWH and HCV-­seropositive PLWH, although the lat- Trends in HIV/HCV coinfection, 2015–­2019 ter were, on average, 7 years older than the former. The frequency of IDU was significantly higher among HCV-­ We compared the 2019 results with those from studies car- seropositive PLWH than among HCV-­seronegative ried out yearly from 2015 to 2018 in a similar number of TABLE 1 Baseline characteristics of the 1325 individuals with HIV included in the study HCV antibodies Positive Total HIV MEDICINE HCV RNA-­negative HCV RNA-­negative spontaneous HCV RNA Total HCV Unknown HCV RNA+ post treatment clearance unknown positive Negative Characteristic N=9 N = 29 N = 291 N = 55 N=1 N = 376 N = 940 pa N = 1325 Sex [n (%)] Male 8 (88.9) 23 (79.3) 224 (77.0) 34 (61.8) 1 (100.0) 282 (75.0) 709 (75.4) 0.894 999 (75.4) Female 0 6 (20.7) 67 (23.0) 20 (36.4) 0 93 (24.7) 227 (24.1) 320 (24.1) Unknown 1 (11.1) 0 0 1 (1.8) 0 1 (0.3) 4 (0.4) 6 (0.5) Age (years) [mean (SD)] 50 (18) 53 (7) 54 (7) 54 (7) 64 (-­) 54 (7) 47 (12) < 0.001 49 (12) HIV transmission category [n (%)] Injection drug use 0 25 (86.2) 231 (79.4) 40 (72.7) 0 296 (78.7) 44 (4.7) < 0.001 340 (25.7) Heterosexual 2 (22.2) 2 (6.9) 18 (6.2) 9 (16.4) 0 29 (7.7) 307 (32.7) 338 (25.5) MSM 5 (55.6) 2 (6.9) 24 (8.2) 3 (5.4) 0 29 (7.7) 500 (53.2) 534 (40.3) Contaminated blood products 0 0 6 (2.1) 1 (1.8) 0 7 (1.9) 4 (0.4) 11 (0.8) Mother-­to-­child transmission 0 0 2 (0.7) 0 0 2 (0.5) 17 (1.8) 19 (1.4) Other 2 (22.2) 0 9 (3.1) 2 (3.6) 1 (100.0) 12 (3.2) 67 (7.1) 81 (6.1) Unknown 0 0 1 (0.3) 0 0 1 (0.3) 1 (0.1) 2 (0.2) CDC clinical category C [n (%)] No 6 (66.7) 17 (58.6) 219 (75.3) 39 (70.9) 1 (100.0) 276 (73.4) 758 (80.6) 0.015 1040 (78.5) Yes 2 (22.2) 11 (37.9) 70 (24.0) 13 (23.6) 0 94 (25.0) 172 (18.3) 268 (20.2) Unknown 1 (11.1) 1 (3.5) 2 (0.7) 3 (5.5) 0 6 (1.6) 10 (1.1) 17 (1.3) HBsAg [n (%)] Negative 3 (33.3) 25 (86.2) 274 (94.2) 49 (89.1) 1 (100.0) 349 (92.8) 904 (96.2) 0.036 1256 (94.8) Positive 0 2 (6.9) 10 (3.4) 4 (7.3) 0 16 (4.3) 22 (2.3) 38 (2.9) Unknown 6 (66.7) 2 (6.9) 7 (2.4) 2 (3.6) 0 11 (2.9) 14 (1.5) 31 (2.3) ART [n (%)] No 0 0 5 (1.7) 3 (5.5) 0 8 (2.1) 13 (1.4) 0.024 21 (1.6) Yes 8 (88.9) 29 (100.0) 283 (97.3) 51 (92.7) 1 (100.0) 364 (96.8) 926 (98.5) 1298 (98.0) Unknown 1 (11.1) 0 3 (1.0) 1 (1.8) 0 4 (1.1) 1 (0.1) 6 (0.4) |     (Continues) 709 14681293, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13229 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License TABLE 1 (Continued) 710 HCV antibodies |    Positive Total HCV RNA-­negative HCV RNA-­negative spontaneous HCV RNA Total HCV Unknown HCV RNA+ post treatment clearance unknown positive Negative Characteristic N=9 N = 29 N = 291 N = 55 N=1 N = 376 N = 940 pa N = 1325 Category of ART regimen [n (%)] First-­line therapy 1 (12.5) 4 (13.8) 10 (3.5) 4 (7.8) 0 18 (4.9) 163 (17.6) < 0.001 182 (14.0) Switch unrelated to toxicity/ 3 (37.5) 17 (58.6) 172 (60.8) 36 (70.6) 1 (100.0) 226 (62.1) 546 (59.0) 775 (59.7) failure Switch following failure 2 (25.0) 3 (10.3) 21 (7.4) 3 (5.9) 0 27 (7.4) 45 (4.9) 74 (5.7) Switch following toxicity 2 (25.0) 5 (17.2) 72 (25.4) 7 (13.7) 0 84 (23.1) 155 (16.7) 241 (18.6) Clinical trial 0 0 4 (1.4) 1 (2.0) 0 5 (1.4) 15 (1.6) 20 (1.5) Unknown 0 0 4 (1.4) 0 0 4 (1.1) 2 (0.2) 6 (0.5) Type of ART regimen [n (%)] Two NRTIs + one NNRTI 1 (12.5) 0 47 (16.6) 13 (25.5) 0 60 (16.5) 190 (20.5) 0.034 251 (19.3) Two NRTIs + one PI 1 (12.5) 13 (44.8) 49 (17.3) 9 (17.6) 0 71 (19.5) 123 (13.3) 195 (15.0) Two NRTIs + one integrase 5 (62.5) 11 (37.9) 121 (42.8) 19 (37.2) 0 151 (41.5) 446 (48.2) 602 (46.4) inhibitor Dual therapy: DTG + 3TC or RPV 0 1 (3.4) 25 (8.8) 1 (2.0) 1 (100.0) 28 (7.7) 59 (6.4) 87 (6.7) Dual therapy: PI + 3TC 0 0 9 (3.2) 3 (5.9) 0 12 (3.3) 25 (2.7) 37 (2.8) Other dual therapy combinations 1 (12.5) 1 (3.4) 11 (3.9) 5 (9.8) 0 17 (4.7) 32 (3.5) 50 (3.8) PI-­based monotherapy 0 0 13 (4.6) 1 (2.0) 0 14 (3.8) 23 (2.5) 37 (2.8) Other 0 3 (10.3) 8 (2.8) 0 0 11 (3.0) 28 (3.0) 39 (3.0) CD4+ –­ T cells/μL [median (IQR)] All patients 809 604 (365–­744) 640 (398–­872) 691 (470–­881) 724 (724–­724) 643 707 (530–­ < 0.001 694 (510–­920) (404–­866) 947) (481–­930) Patients on ART 809 604 (365–­744) 640 (398–­867) 669 (470–­890) 724 (724–­724) 640 710 (536–­ < 0.001 696 (510–­920) (402–­866) 951) (486–­930) FANCIULLI et al. 14681293, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13229 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HIV MEDICINE TABLE 1 (Continued) HCV antibodies Positive Total HCV RNA-­negative HCV RNA-­negative spontaneous HCV RNA Total HCV Unknown HCV RNA+ post treatment clearance unknown positive Negative Characteristic N=9 N = 29 N = 291 N = 55 N=1 N = 376 N = 940 pa N = 1325 HIV RNA copies/mL [n (%)] All patients < 50 8 (88.9) 23 (79.3) 266 (91.4) 53 (96.4) 1 (100.0) 343 (91.2) 861 (91.6) 0.860 1212 (91.5) 50–­200 0 2 (6.9) 13 (4.5) 0 0 15 (4.0) 42 (4.5) 57 (4.3) > 200 0 4 (13.8) 10 (3.4) 2 (3.6) 0 16 (4.3) 34 (3.6) 50 (3.8) Unknown 1 (11.1) 0 2 (0.7) 0 0 2 (0.5) 3 (0.3) 6 (0.4) Patients on ART < 50 8 (100.0) 23 (79.3) 262 (92.6) 50 (98.0) 1 (100.0) 336 (92.3) 858 (92.7) 0.516 1202 (92.6) 50–­200 0 2 (6.9) 11 (3.9) 0 0 13 (3.6) 42 (4.5) 55 (4.2) > 200 0 4 (13.8) 9 (3.2) 1 (2.0) 0 14 (3.8) 23 (2.5) 37 (2.9) Unknown 0 0 1 (0.3) 0 0 1 (0.3) 3 (0.3) 4 (0.3) Abbreviations: ART, antiretroviral therapy; CDC, Centers for Disease Control and Prevention; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; IQR, interquartile range; MSM, men who have sex with men; NNRTI, nonnucleoside reverse-­transcriptase inhibitor; NRTI, nucleoside reverse-­transcriptase inhibitor; PI, protease inhibitor; RNA, ribonucleic acid; SD, standard deviation. a p-­values for the comparisons between HCV-­positive patients (N = 385) and HCV-­negative patients (N = 940) derived from the χ2 test for independence for categorical variables and the t-­test or the nonparametric Mann–­Whitney test for normally or non-­normally distributed continuous variables, respectively. |     711 14681293, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13229 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License |    14681293, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13229 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 712 FANCIULLI et al. centres distributed throughout Spain [20–­23]. A summary total burden of HCV infection among PLWH. Decreasing of participating centres, the reference population and the trends in HCV markers, particularly HCV-­RNA, were ob- sample size of the previous GeSIDA prevalence studies is served among IDUs (from 55.7% in 2015 to 7.3% in 2019) shown in Table 2. and those in other/unknown transmission categories Men who have sex with men and IDU were the main (from 13.4% in 2015 to 0.4% in 2019). A decreasing trend in HIV transmission categories among PLWH in all the prev- HCV markers of infection was not observed among MSM. alence studies. From 2015 to 2019, the proportion of MSM In this group, the prevalence of active HCV infection re- increased from 35.1% to 40.3% (p trend = 0.004), and the mained under 2.5% throughout the study period, with a proportion of IDU declined from 30.7% to 25.7% (p trend peak of 2.2% in 2016 and a trough of 0.4% in 2019. = 0.004) (Figure S1). As shown in Figure 3, uptake of anti-­HCV treatment Prevalence trends of anti-­HCV antibodies and active increased significantly from 59.3% in 2015 to 95.0% in HCV infections among PLWH from 2015 to 2019 are 2016. shown in Figure 1. The prevalence of anti-­HCV antibod- ies decreased steadily from 37.7% in 2015 to 28.6% in 2019 (p trend < 0.001), whereas the prevalence of active HCV DISC USSION infection decreased sharply from 22.1% in 2015 to 2.2% in 2019 (p trend < 0.001). In this cross-­sectional study performed in Spain at the Prevalence trends of HCV seropositivity and active HCV end of 2019, almost one-­third of PLWH were seropositive infections among PLWH categorized by HIV transmission for HCV, and approximately 2% had active HCV infec- category groups are shown in Figure 2. Over the years, tion. We also found that over the period 2015–­2019, the HCV coinfection has been at its highest in those acquir- prevalence of active HCV declined by 90% and the uptake ing HIV by IDU, while MSM have contributed little to the of DAA treatment increased significantly, reaching 95%. T A B L E 2 Centres and patients included in the nationwide hepatitis C virus (HCV) prevalence studies carried out by the ‘Grupo de Estudio del SIDA’ (GeSIDA) (2015–­2019) Year [reference] 2015 2016 2017 2018 2019 Centres 41 43 43 43 41 Reference population 35 791 38 904 40 322 40 650 41 973 Sample size 1867 1588 1690 1733 1325 Tested for HCV antibodies 98.7% 99.8% 99.1% 99.3% 99.3% F I G U R E 1 Prevalence of hepatitis C virus (HCV) seropositivity and active HCV infection in the annual cross-­sectional studies carried out by ‘Grupo de Estudio del SIDA’ (GeSIDA) from 2015 to 2019. HCV Ab+, presence of antibodies against HCV; HCV-­RNA+, detectable HCV-­RNA | 14681293, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13229 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HIV MEDICINE     713 F I G U R E 2 Prevalence of hepatitis C virus (HCV) seropositivity and active HCV infection in the annual cross-­sectional studies carried out by ‘Grupo de Estudio del SIDA’ (GeSIDA) from 2015 to 2019, categorized by HIV transmission category groups. HCV Ab+, presence of antibodies against HCV; HCV-­RNA+, detectable HCV-­RNA, IDU, injection drug use; MSM, men who have sex with men contributing to this decrease in the first 15 years of this century was the decline in IDU as a mechanism of HIV transmission [12] owing to preventive drug programmes [26]. The higher mortality rates in HCV-­infected PLWH than in non-­HCV-­infected PLWH and the anti-­HCV treat- ment available during this period also helped to decrease the prevalence of HCV infection [13]. Notwithstanding this, the main factor contributing to the sharp reduction in active HCV infection found in recent years in Spain has been the increased uptake of treatment with DAAs, an approach whose effectiveness among HCV-­infected PLWH has been > 90% [27]. In 2015, Spain implemented a National Strategic Plan for chronic hepatitis C, which con- F I G U R E 3 Uptake of anti-­hepatitis C virus (HCV) treatment templated that all HCV-­infected patients were eligible for in the annual cross-­sectional studies carried out by the ‘Grupo de DAA therapy. However, due to the extent of HCV infec- Estudio del SIDA’ (GeSIDA) from 2015 to 2019. Treatment uptake tion in Spain, it was decided to prioritize patients with ad- was defined as the proportion of people living with HIV with vanced liver fibrosis or cirrhosis, transplant recipients or current or past chronic HCV infection exposed to anti-­HCV therapy patients on transplant waiting lists, and those with a high risk of transmission such as MSM with ongoing transmis- sion behaviours. Universal access to DAA therapy was The prevalence of HCV seropositivity and active HCV in- approved in June 2017, including acute/recent infections fection found among PLWH in 2019 are 41 and 13 times and reinfections. higher than the prevalence among the general population In 2019, most active HCV infections in PLWH were in Spain (0.69% and 0.17%, respectively) [24], underscor- chronic and were detected among those involved in IDU, ing yet again that PLWH comprise a population that is at whereas fewer than 10% were identified among MSM. In higher risk of infection by HCV. a European survey performed in 2015, those involved in After introduction of highly active ART, coinfection by IDU were the leading HCV-­seropositive PLWH population HCV emerged as a leading cause of morbidity and mor- group, whereas the proportion of MSM varied from 16.3% tality among PLWH in Spain, a country where IDU was in southern Europe to 36.4% in northern Europe [28]. It the primary driver of the HIV epidemic for many years is notable that, in the GeSIDA 2019 study, almost one-­ [12]. In the first nationwide cross-­sectional study on quarter of PLWH who cleared HCV following anti-­HCV HCV performed by GeSIDA in 2002, the prevalence rates therapy had liver cirrhosis, indicating that the burden of of HCV seropositivity and active HCV infection among HCV-­related cirrhosis will remain a substantial problem PLWH were 61% and 54%, respectively [25], which fell to even if the desired goal of eliminating HCV among this 38% and 22%, respectively, in 2015 [20]. The main factor population group is achieved. |    14681293, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13229 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 714 FANCIULLI et al. Taken together, the results of the GeSIDA studies in- AR-­R reports honoraria for advice or public speaking dicate that Spain is on the right track towards achiev- from AbbVie, Gilead, MSD, Janssen and ViiV Healthcare, ing microelimination of HCV among PLWH. However, and grants from AbbVie, Gilead, MSD, Janssen and ViiV achieving this goal is not without its obstacles, mainly Healthcare. IJ reports honoraria for advice or public because of ongoing risk transmission behaviours among speaking from Gilead and ViiV Healthcare. JGG reports MSM. Although MSM contributed little to the total bur- honoraria for advice or public speaking from AbbVie, den of HCV infection among PLWH, it is noteworthy Gilead, MSD, Janssen and ViiV Healthcare, and grants that in contrast to the sharp decline in active HCV infec- from Gilead, MSD and ViiV Healthcare. The rest of the tions among those involved in IDU, a clear decreasing authors have nothing to disclose. trend was not observed among MSM. Besides, real-­world data for PLWH who received all-­oral DAA as treatment AUTHOR CONTRIBUTIONS for HCV in Spain have shown reinfection rates 28 times JB and JGG conceived of the work. JB, MdM, JB, and JGG higher for MSM than for IDU [14]. Our study reveals ad- designed the database. IJ analysed the data. All authors in- ditional obstacles to eliminating HCV. In 2019, almost terpreted the data. JB drafted the manuscript. All authors half of PLWH with active HCV infection were receiving critically revised the manuscript for important intellectual or were programmed to receive DAA therapy; among the content and gave final approval. The authors agree to be other half, the main reasons for not being on or not hav- accountable for all aspects of the work in ensuring that ing programmed therapy were unknown/loss to follow-­up questions related to the accuracy or integrity of any part or physician decision, whereas patient refusal was un- of the work are appropriately investigated and resolved. common. This finding emphasizes the importance of ad- dressing patient-­related and healthcare provider-­related ORCID barriers to and misconceptions regarding HCV treatment Juan Berenguer https://orcid.org/0000-0001-8541-8200 [29]. Pere Domingo https://orcid.org/0000-0003-1138-5770 The design of our study was limited mainly by its in- Jordi Navarro https://orcid.org/0000-0002-7187-0367 ability to assess the incidence of HCV infection, which can only be appraised within a prospective cohort. However, REFERENCES repeated cross-­sectional studies over time in a defined 1. Sulkowski MS, Mast EE, Seeff LB, Thomas DL. Hepatitis C virus population (not necessarily the same individuals) provide infection as an opportunistic disease in persons infected with a measure of incidence and are frequently used by pub- human immunodeficiency virus. Clin Infect Dis. 2000;30(Suppl 1):S77-­S84. lic health agencies to assess secular trends in infection or 2. Boesecke C, Rockstroh JK. Acute hepatitis C in patients with changes in disease burden [30]. HIV. Semin Liver Dis. 2012;32(2):130-­137. In conclusion, this study showed that the prevalence 3. 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