Abstract
In 2016, the World Health Organization (WHO) introduced global targets for the elimination of hepatitis C virus (HCV) by 2030. We conducted a nationwide HCV micro-elimination program among men who have sex with men (MSM) living with human immunodeficiency virus (HIV) from the Swiss HIV Cohort Study (SHCS) to test whether the WHO goals are achievable in this population.
During phase A (10/2015–06/2016), we performed a population-based and systematic screening for HCV-RNA among MSM from the SHCS. During phase B (06/2016–02/2017) we offered treatment with HCV direct-acting antiviral (DAA) agents to MSM identified with a replicating HCV infection. During phase C (03/2017–11/2017), we offered rescreening to all MSM for HCV-RNA and initiated DAA treatment in MSM with replicating infections.
We screened 3715/4640 (80%) MSM and identified 177 with replicating HCV infections (4.8%); 150 (85%) of whom started DAA treatment and 149 (99.3%) were cured. We rescreened 2930/3538 (83%) MSM with a prior negative HCV-RNA and identified 13 (0.4%) with a new HCV infection. At the end of the micro-elimination program, 176/190 MSM (93%) were cured, and the HCV incidence rate declined from .53 per 100 patient-years (95% CI, .35–.83) prior to the intervention to .12 (95% CI, .03–.49) by the end of 2019.
A systematic, population-based HCV micro-elimination program among MSM living with HIV was feasible and resulted in a strong decline in HCV incidence and prevalence. Our study can serve as a model for other countries aiming to achieve the WHO HCV elimination targets.
NCT02785666.
Viral hepatitis is now a leading cause of death among people suffering from communicable diseases worldwide, surpassing human immunodeficiency virus (HIV), tuberculosis, and malaria [1]. Among cases of viral hepatitis, hepatitis C virus (HCV) infection is the leading cause of liver-related mortality [2]. As a response to this global epidemic, in 2016 the World Health Organization (WHO) released its first global strategy on viral hepatitis by calling for the elimination of HCV [3]. The WHO targets for HCV in 2020 and 2030 are to achieve a 30% and 80% reduction in new HCV infections and a 10% and a 65% reduction in HCV-related deaths, respectively [3]. However, the prospect of HCV elimination is extremely challenging because of the scale, complexity, and cost of elimination strategies [4, 5]. Therefore, one pragmatic approach is to break down elimination goals into smaller goals for population segments with specific characteristics, referred to as micro-elimination [6].
The WHO action plan states that micro-elimination efforts should include people living with HIV and specific attention should be paid to men who have sex with men (MSM) practicing risky sexual behaviors. Within this population, HCV infection incidence is particularly high and HCV epidemics among HIV-seropositive MSM have been observed in recent years [7, 8]. As an example, in the Swiss HIV Cohort Study (SHCS) from 2006 to 2012, 74% of incident HCV infections were identified in MSM, whereas the incidence rate dropped in people who inject drugs (PWID) and remained stable in heterosexuals [8].
Recognizing this new HCV epidemic within the SHCS, we conducted the Swiss HCVree Trial with the goal of implementing a population-based systematic HCV micro-elimination program among MSM living with HIV within the SHCS [9, 10]. We concentrated on HIV-diagnosed MSM, as data show that the HCV transmission in Switzerland occurred mainly among this group [8, 11]. The aim of our study was to test whether WHO HCV elimination targets are achievable in clinical practice among MSM living with HIV.
METHODS
Swiss HCVree Trial and Swiss HIV Cohort Study
The Swiss HCVree Trial was designed as a nationwide prospective, multicenter, interventional trial (NCT 02785666) in the framework of the SHCS [12]. In the SHCS, sexually active MSM are yearly screened for HCV antibodies. In all other MSM, HCV antibody testing is done every 2 years.
The Swiss HCVree Trial consisted of 3 phases:
During phase A (10/2015–06/2016), all SHCS physicians and study nurses were asked to test MSM from the SHCS for HCV-RNA [9].
During phase B (06/2016–02/2017), direct-acting antiviral (DAA) treatment was provided to all MSM with a replicating infection regardless of fibrosis stage [10]. Details about the study treatment are provided in the Supplementary Material.
During phase C (03/2017–11/2017), SHCS physicians and study nurses were asked to test again all MSM for HCV-RNA.
Local ethics committees of all participating study sites approved the study and written consent was obtained from all participants.
Study Population and Study Measurements
All MSM enrolled in the SHCS were eligible to participate in the study. MSM were defined as male participants reporting a homosexual or bisexual HIV-transmission mode and/or a sexual preference at SHCS enrollment. MSM attending a clinical visit during phases A and C were systematically screened for HCV-RNA. HCV-RNA testing was performed using the Abbott RealTime HCV with a limit of quantification of 12 IU/mL. HCV antibodies were measured from all HCV-RNA–positive samples. Detailed information on phases A and B is published elsewhere [9, 10].
Retrospective HCV Testing in the Swiss HIV Cohort Study Database
After completion of the trial, we retrospectively retrieved information on HCV testing (ie, recorded HCV antibodies and/or HCV-RNA results) and DAA treatment of MSM not screened during phases A and C from the SHCS database. This allowed us to improve the representativeness of the estimates for HCV prevalence and incidence at the population level. Detailed information is provided in the Supplementary Material.
Definition of HCV Infection, Type of HCV Infection, and HCV Incidence
Replicating HCV infection was defined as an HCV-RNA result of 100 International Units (IE)/mL or greater [9]. The definition of different types of HCV infections is provided in the Supplementary Material. The incidence of new HCV infections expressed in 100 patient-years (py) was calculated by using the midpoint of the last negative and the first positive HCV-RNA and/or anti–HCV-immunoglobulin G (-IgG) test, whichever came first, and the incidence of HCV reinfection by using the midpoint of the last negative HCV-RNA and the first positive HCV-RNA test.
Phylogenetic Analyses of Incident HCV Infections
Incident genotype 1a HCV infections identified during phase C were sequenced using Illumina technology. Maximum-likelihood phylogenetic trees, containing a fragment of the NB5B region of these and other circulating strains, were built. The strains were retrieved from national and international databases [13].
Statistical Analysis
Statistical analysis was performed using Stata version 15.1 (StataCorp, College Station, TX). Bivariate P values were calculated using Fisher’s exact test for categorical variables and Wilcoxon test or Kruskal-Wallis test for continuous variables. The incidence rate was calculated by tabulating the number of incident infections for patients screened during both phases A and C, with the time-at-risk calculated as between the dates of blood sampling in phases A and C. The 95% confidence intervals (CIs) were calculated using the quadratic approximation to the Poisson log likelihood for the log-rate parameters. Statistical significance was set at P ≤ .05.
RESULTS
Screening Phase A
Prior to phase A (as of 1 June 2015), 9128 individuals with ongoing follow-up were recorded in the SHCS database, of whom 4640 (51%) were MSM (Figure 1A). During phase A, we screened 3715 (80%) MSM for HCV-RNA and identified 177 with a replicating HCV infection, thus suggesting a phase A prevalence of 4.8%. The reasons for a missed HCV screening are published elsewhere [9]. Of those 177 MSM with a positive HCV-RNA screen, 147 (83%) were prevalent HCV infections already known to the investigators prior to phase A (Figure 2). The remaining 30 (17%) HCV infections were not previously diagnosed: 24 (80%) were incident primary HCV infections and 6 (20%) were incident HCV reinfections (Figure 2). Eight patients with an incident primary HCV infection (27%) had a negative HCV antibody test at the time of the positive HCV-RNA screen [9]. Information on HCV test frequency among the MSM in the SHCS prior to phase A as well on the incident HCV infection date is provided in the Supplementary Material.
A, Study flowchart of the Swiss HCVree trial. The dashed blue line subdivides the trial phase A from phase C. MSM from the SHCS were systematically screened for HCV-RNA in both trial phases A and C. For MSM not screened during phase A (n = 925) and C (n = 608) data were retrospectively retrieved from the SHCS database as depicted in panel B. B, Information from the SHCS database for MSM with a missed HCV screening during phases A and C. For 925 and 608 MSM not screened during phase A and C, respectively, data on HCV serostatus and HCV-RNA were retrospectively retrieved from the SHCS database. The dashed blue line subdivides the trial phase A from phase C. Abbreviations: Ab, antibody; HCV, hepatitis C virus; MSM, men who have sex with men; SHCS, Swiss HIV Cohort Study.
Prevalent and incident replicating HCV infections stratified by the trial phases A and C. Incident infections include incident primary HCV infections (n = 24) and incident HCV reinfections (n = 6). Abbreviation: HCV, hepatitis C virus.
The baseline characteristics of MSM included in the Swiss HCVree Trial stratified by the different study phases and the HCV screening state are shown in Table 1. Factors significantly associated with a missed HCV screen during either phase A or C included older age, not reporting intravenous drug use, and being followed by a SHCS private physician (Table 1). For those MSM not screened during phase A, the HCV antibody status was retrospectively retrieved from the SHCS database for 919 (99%) of the 926 individuals. Of those 919 MSM, 861 (94%) had a negative HCV antibody test recorded in the SHCS database during their regular SHCS follow-up (Figure 1B). However, 58 MSM (6%) had a positive HCV antibody test: 33 (57%) with an undetectable HCV-RNA, 24 (41%) with a detectable HCV-RNA, and 1 (2%) without information on the HCV-RNA.
Baseline Characteristics of Patients Included in the Swiss HCVree Trial Stratified by the Different Study Phases and the Hepatitis C Virus Screening State
| Phase A | Phase C | |||||||
|---|---|---|---|---|---|---|---|---|
| Unscreened (n = 925) | Screened, Negative (n = 3538) | Screened, Positive (n = 177) | P | Unscreened (n = 608) | Screened, Negative (n = 3071) | Screened, Positive (n = 36) | P | |
| Age, median [IQR], years | 49 [39–56] | 49 [42–56] | 47 [40–54] | .007a | 50 [42–57] | 51 [43–57] | 50 [45–53] | .509a |
| Ethnicity, n (%) | ||||||||
| White | 813 (87.9) | 3201 (90.5) | 160 (90.4) | .162b | 542 (89.1) | 2728 (88.8) | 31 (86.1) | .354b |
| Black | 24 (2.6) | 54 (1.5) | 6 (3.4) | 15 (2.5) | 44 (1.4) | 1 (2.8) | ||
| Asian | 60 (6.5) | 148 (4.2) | 4 (2.3) | 32 (5.3) | 118 (3.8) | 2 (5.6) | ||
| Latino | 24 (2.6) | 128 (3.6) | 7 (4.0) | 16 (2.6) | 117 (3.8) | 2 (5.6) | ||
| Ever on ART, n (%) | ||||||||
| Yes | 911 (98.5) | 3518 (99.4) | 176 (99.4) | 1.000b | 602 (99.0) | 3056 (99.5) | 36 (100.0) | 1.000b |
| No | 14 (1.5) | 20 (0.6) | 1 (0.6) | 6 (1.0) | 15 (0.5) | 0 (0) | ||
| Ever reported intravenous drug use, n (%) | ||||||||
| Yes | 12 (1.3) | 34 (1.0) | 24 (13.6) | <.001b | 23 (3.9) | 109 (3.5) | 11 (30.6) | <.001b |
| No | 913 (98.7) | 3503 (99.0) | 153 (86.4) | 584 (96.1) | 2962 (96.5) | 25 (69.4) | ||
| SHCS center | ||||||||
| Tertiary hospital | 397 (42.9) | 2113 (59.7) | 88 (49.7) | 308 (50.7) | 1869 (60.9) | 24 (66.7) | .871b | |
| Nontertiary hospital | 100 (10.8) | 189 (5.3) | 22 (12.4) | <.001b | 38 (6.3) | 172 (5.6) | 1 (2.8) | |
| Private physicians | 316 (34.2) | 855 (24.2) | 50 (28.2) | 181 (29.8) | 716 (23.3) | 8 (22.2) | ||
| CD4 nadir, cells per µL, median [IQR] | 322 [194–569] | 292 [177–478] | 295 [193–509] | .398a | 300 [179–508] | 291 [178–480] | 335 [209–616] | .723b |
| Prior AIDS diagnosis, n (%) | 137 (14.8) | 654 (18.5) | 30 (16.9) | .678c | 127 (20.9) | 566 (18.4) | 7 (19.4) | .353a |
| CD4 at baseline, cells per µL, median [IQR] | 607 [463–782] | 628 [476–824] | 622 [450–773] | .178a | 632 [472–823] | 66 [510–854] | 654 [526–826] | 1.000c |
| HIV RNA at baseline <50 copies/mL, n (%) | 736 (87.2) | 3298 (93.6) | 156 (91.8) | .336b | 566 (93.2) | 2984 (97.2) | 32 (88.9) | .658a |
| HIV subtype, n (%) | ||||||||
| Subtype B | 600 (84.5) | 2632 (89.3) | 130 (90.1) | .676b | 414 (84.5) | 2323 (90.2) | 28 (84.8) | .015b |
| Other subtypes | 110 (15.5) | 316 (10.7) | 13 (8.9) | 76 (15.5) | 252 (9.8) | 5 (15.2) | ||
| Phase A | Phase C | |||||||
|---|---|---|---|---|---|---|---|---|
| Unscreened (n = 925) | Screened, Negative (n = 3538) | Screened, Positive (n = 177) | P | Unscreened (n = 608) | Screened, Negative (n = 3071) | Screened, Positive (n = 36) | P | |
| Age, median [IQR], years | 49 [39–56] | 49 [42–56] | 47 [40–54] | .007a | 50 [42–57] | 51 [43–57] | 50 [45–53] | .509a |
| Ethnicity, n (%) | ||||||||
| White | 813 (87.9) | 3201 (90.5) | 160 (90.4) | .162b | 542 (89.1) | 2728 (88.8) | 31 (86.1) | .354b |
| Black | 24 (2.6) | 54 (1.5) | 6 (3.4) | 15 (2.5) | 44 (1.4) | 1 (2.8) | ||
| Asian | 60 (6.5) | 148 (4.2) | 4 (2.3) | 32 (5.3) | 118 (3.8) | 2 (5.6) | ||
| Latino | 24 (2.6) | 128 (3.6) | 7 (4.0) | 16 (2.6) | 117 (3.8) | 2 (5.6) | ||
| Ever on ART, n (%) | ||||||||
| Yes | 911 (98.5) | 3518 (99.4) | 176 (99.4) | 1.000b | 602 (99.0) | 3056 (99.5) | 36 (100.0) | 1.000b |
| No | 14 (1.5) | 20 (0.6) | 1 (0.6) | 6 (1.0) | 15 (0.5) | 0 (0) | ||
| Ever reported intravenous drug use, n (%) | ||||||||
| Yes | 12 (1.3) | 34 (1.0) | 24 (13.6) | <.001b | 23 (3.9) | 109 (3.5) | 11 (30.6) | <.001b |
| No | 913 (98.7) | 3503 (99.0) | 153 (86.4) | 584 (96.1) | 2962 (96.5) | 25 (69.4) | ||
| SHCS center | ||||||||
| Tertiary hospital | 397 (42.9) | 2113 (59.7) | 88 (49.7) | 308 (50.7) | 1869 (60.9) | 24 (66.7) | .871b | |
| Nontertiary hospital | 100 (10.8) | 189 (5.3) | 22 (12.4) | <.001b | 38 (6.3) | 172 (5.6) | 1 (2.8) | |
| Private physicians | 316 (34.2) | 855 (24.2) | 50 (28.2) | 181 (29.8) | 716 (23.3) | 8 (22.2) | ||
| CD4 nadir, cells per µL, median [IQR] | 322 [194–569] | 292 [177–478] | 295 [193–509] | .398a | 300 [179–508] | 291 [178–480] | 335 [209–616] | .723b |
| Prior AIDS diagnosis, n (%) | 137 (14.8) | 654 (18.5) | 30 (16.9) | .678c | 127 (20.9) | 566 (18.4) | 7 (19.4) | .353a |
| CD4 at baseline, cells per µL, median [IQR] | 607 [463–782] | 628 [476–824] | 622 [450–773] | .178a | 632 [472–823] | 66 [510–854] | 654 [526–826] | 1.000c |
| HIV RNA at baseline <50 copies/mL, n (%) | 736 (87.2) | 3298 (93.6) | 156 (91.8) | .336b | 566 (93.2) | 2984 (97.2) | 32 (88.9) | .658a |
| HIV subtype, n (%) | ||||||||
| Subtype B | 600 (84.5) | 2632 (89.3) | 130 (90.1) | .676b | 414 (84.5) | 2323 (90.2) | 28 (84.8) | .015b |
| Other subtypes | 110 (15.5) | 316 (10.7) | 13 (8.9) | 76 (15.5) | 252 (9.8) | 5 (15.2) | ||
Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; IQR, interquartile range; SHCS, Swiss HIV Cohort Study.
aFisher’s exact test between unscreened and screened populations.
bChi-square test between unscreened and screened populations.
cP value of Chi-squared test between unscreened and screened populations.
Baseline Characteristics of Patients Included in the Swiss HCVree Trial Stratified by the Different Study Phases and the Hepatitis C Virus Screening State
| Phase A | Phase C | |||||||
|---|---|---|---|---|---|---|---|---|
| Unscreened (n = 925) | Screened, Negative (n = 3538) | Screened, Positive (n = 177) | P | Unscreened (n = 608) | Screened, Negative (n = 3071) | Screened, Positive (n = 36) | P | |
| Age, median [IQR], years | 49 [39–56] | 49 [42–56] | 47 [40–54] | .007a | 50 [42–57] | 51 [43–57] | 50 [45–53] | .509a |
| Ethnicity, n (%) | ||||||||
| White | 813 (87.9) | 3201 (90.5) | 160 (90.4) | .162b | 542 (89.1) | 2728 (88.8) | 31 (86.1) | .354b |
| Black | 24 (2.6) | 54 (1.5) | 6 (3.4) | 15 (2.5) | 44 (1.4) | 1 (2.8) | ||
| Asian | 60 (6.5) | 148 (4.2) | 4 (2.3) | 32 (5.3) | 118 (3.8) | 2 (5.6) | ||
| Latino | 24 (2.6) | 128 (3.6) | 7 (4.0) | 16 (2.6) | 117 (3.8) | 2 (5.6) | ||
| Ever on ART, n (%) | ||||||||
| Yes | 911 (98.5) | 3518 (99.4) | 176 (99.4) | 1.000b | 602 (99.0) | 3056 (99.5) | 36 (100.0) | 1.000b |
| No | 14 (1.5) | 20 (0.6) | 1 (0.6) | 6 (1.0) | 15 (0.5) | 0 (0) | ||
| Ever reported intravenous drug use, n (%) | ||||||||
| Yes | 12 (1.3) | 34 (1.0) | 24 (13.6) | <.001b | 23 (3.9) | 109 (3.5) | 11 (30.6) | <.001b |
| No | 913 (98.7) | 3503 (99.0) | 153 (86.4) | 584 (96.1) | 2962 (96.5) | 25 (69.4) | ||
| SHCS center | ||||||||
| Tertiary hospital | 397 (42.9) | 2113 (59.7) | 88 (49.7) | 308 (50.7) | 1869 (60.9) | 24 (66.7) | .871b | |
| Nontertiary hospital | 100 (10.8) | 189 (5.3) | 22 (12.4) | <.001b | 38 (6.3) | 172 (5.6) | 1 (2.8) | |
| Private physicians | 316 (34.2) | 855 (24.2) | 50 (28.2) | 181 (29.8) | 716 (23.3) | 8 (22.2) | ||
| CD4 nadir, cells per µL, median [IQR] | 322 [194–569] | 292 [177–478] | 295 [193–509] | .398a | 300 [179–508] | 291 [178–480] | 335 [209–616] | .723b |
| Prior AIDS diagnosis, n (%) | 137 (14.8) | 654 (18.5) | 30 (16.9) | .678c | 127 (20.9) | 566 (18.4) | 7 (19.4) | .353a |
| CD4 at baseline, cells per µL, median [IQR] | 607 [463–782] | 628 [476–824] | 622 [450–773] | .178a | 632 [472–823] | 66 [510–854] | 654 [526–826] | 1.000c |
| HIV RNA at baseline <50 copies/mL, n (%) | 736 (87.2) | 3298 (93.6) | 156 (91.8) | .336b | 566 (93.2) | 2984 (97.2) | 32 (88.9) | .658a |
| HIV subtype, n (%) | ||||||||
| Subtype B | 600 (84.5) | 2632 (89.3) | 130 (90.1) | .676b | 414 (84.5) | 2323 (90.2) | 28 (84.8) | .015b |
| Other subtypes | 110 (15.5) | 316 (10.7) | 13 (8.9) | 76 (15.5) | 252 (9.8) | 5 (15.2) | ||
| Phase A | Phase C | |||||||
|---|---|---|---|---|---|---|---|---|
| Unscreened (n = 925) | Screened, Negative (n = 3538) | Screened, Positive (n = 177) | P | Unscreened (n = 608) | Screened, Negative (n = 3071) | Screened, Positive (n = 36) | P | |
| Age, median [IQR], years | 49 [39–56] | 49 [42–56] | 47 [40–54] | .007a | 50 [42–57] | 51 [43–57] | 50 [45–53] | .509a |
| Ethnicity, n (%) | ||||||||
| White | 813 (87.9) | 3201 (90.5) | 160 (90.4) | .162b | 542 (89.1) | 2728 (88.8) | 31 (86.1) | .354b |
| Black | 24 (2.6) | 54 (1.5) | 6 (3.4) | 15 (2.5) | 44 (1.4) | 1 (2.8) | ||
| Asian | 60 (6.5) | 148 (4.2) | 4 (2.3) | 32 (5.3) | 118 (3.8) | 2 (5.6) | ||
| Latino | 24 (2.6) | 128 (3.6) | 7 (4.0) | 16 (2.6) | 117 (3.8) | 2 (5.6) | ||
| Ever on ART, n (%) | ||||||||
| Yes | 911 (98.5) | 3518 (99.4) | 176 (99.4) | 1.000b | 602 (99.0) | 3056 (99.5) | 36 (100.0) | 1.000b |
| No | 14 (1.5) | 20 (0.6) | 1 (0.6) | 6 (1.0) | 15 (0.5) | 0 (0) | ||
| Ever reported intravenous drug use, n (%) | ||||||||
| Yes | 12 (1.3) | 34 (1.0) | 24 (13.6) | <.001b | 23 (3.9) | 109 (3.5) | 11 (30.6) | <.001b |
| No | 913 (98.7) | 3503 (99.0) | 153 (86.4) | 584 (96.1) | 2962 (96.5) | 25 (69.4) | ||
| SHCS center | ||||||||
| Tertiary hospital | 397 (42.9) | 2113 (59.7) | 88 (49.7) | 308 (50.7) | 1869 (60.9) | 24 (66.7) | .871b | |
| Nontertiary hospital | 100 (10.8) | 189 (5.3) | 22 (12.4) | <.001b | 38 (6.3) | 172 (5.6) | 1 (2.8) | |
| Private physicians | 316 (34.2) | 855 (24.2) | 50 (28.2) | 181 (29.8) | 716 (23.3) | 8 (22.2) | ||
| CD4 nadir, cells per µL, median [IQR] | 322 [194–569] | 292 [177–478] | 295 [193–509] | .398a | 300 [179–508] | 291 [178–480] | 335 [209–616] | .723b |
| Prior AIDS diagnosis, n (%) | 137 (14.8) | 654 (18.5) | 30 (16.9) | .678c | 127 (20.9) | 566 (18.4) | 7 (19.4) | .353a |
| CD4 at baseline, cells per µL, median [IQR] | 607 [463–782] | 628 [476–824] | 622 [450–773] | .178a | 632 [472–823] | 66 [510–854] | 654 [526–826] | 1.000c |
| HIV RNA at baseline <50 copies/mL, n (%) | 736 (87.2) | 3298 (93.6) | 156 (91.8) | .336b | 566 (93.2) | 2984 (97.2) | 32 (88.9) | .658a |
| HIV subtype, n (%) | ||||||||
| Subtype B | 600 (84.5) | 2632 (89.3) | 130 (90.1) | .676b | 414 (84.5) | 2323 (90.2) | 28 (84.8) | .015b |
| Other subtypes | 110 (15.5) | 316 (10.7) | 13 (8.9) | 76 (15.5) | 252 (9.8) | 5 (15.2) | ||
Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; IQR, interquartile range; SHCS, Swiss HIV Cohort Study.
aFisher’s exact test between unscreened and screened populations.
bChi-square test between unscreened and screened populations.
cP value of Chi-squared test between unscreened and screened populations.
Overall, 201 out of 4640 MSM had a replicating HCV infection, thus suggesting an overall prevalence of 4.3%. A total of 177 MSM with a replicating HCV infection were identified during screening phase A and 24 by retrieving the samples of participants with missing HCV screening from the SHCS repository.
Treatment Phase B
During the treatment phase B, 150 out of the 177 patients (85%) with a replicating HCV infection were treated with DAAs, of whom 149 (99.3%) achieved sustained virologic response (SVR) 12 [10]. Of the remaining 27 patients, 3 patients showed a spontaneous clearance of the infection and 1 patient died of an opioid overdose unrelated to his HIV-HCV infection. Twenty-three out of 177 MSM (7%) with a replicating infection remained untreated at the end of phase B (Figure 2). The reasons for not being treated were the physician’s decision to postpone treatment (n = 8) and the patient refusing DAA treatment (n = 14) [10]. One patient was lost to follow-up. Of the 24 MSM not screened during phase A, but with a replicating HCV infection according to the retrospective assessment of the SHCS database, 15 (65%) were treated outside of the Swiss HCVree Trial and achieved SVR 12. No information was available on the remaining 9 individuals. The treatment phase was accompanied by a newly developed behavioral intervention tailored towards HCV risk reduction. Details about the behavioral intervention are published elsewhere [10, 14].
Rescreening Phase C
During phase C, we rescreened 2930 (83%) out of the 3538 MSM who had a negative HCV-RNA screening result during phase A (Figure 1A). Of those, 13 (0.4%) had a positive HCV-RNA screening result and therefore were classified as incident primary HCV infection (Figure 2). The remaining 2917 MSM (99.6%) had a negative HCV-RNA screening result. All of the 177 MSM with a replicating HCV infection initially identified during phase A were also rescreened: 154 (87%) had a negative HCV-RNA and 23 had a positive HCV-RNA (Figure 2). These 23 MSM reflect the group of patients not treated during phase B for the reasons stated above.
Of the 3538 MSM screened during phase A, 608 (17%) were not rescreened during phase C (Figure 1A). Of these, between phases A and C, 138 MSM (23%) had left the SHCS for various reasons: 37 left the country, 34 died, 10 discontinued the SHCS, 12 changed to a non-SHCS physician, 38 were lost to follow-up, and for 7 MSM there was no information available. For the remaining 470 MSM not screened during phase C, we were able to retrospectively retrieve the HCV antibody status from the SHCS database for 466 MSM (Figure 1B). Of these 466 MSM, 430 (92%) had a negative HCV antibody test recorded in the SHCS database, whereas 36 MSM (8%) had a positive HCV antibody test: 33 (92%) with a negative HCV-RNA and 3 (8%) with a positive HCV-RNA. For these 3 infections, a prior positive HCV test was recorded in the SHCS database and therefore they were classified as prevalent HCV infections. No information was available on the remaining 4 individuals. In sum, we identified 180 MSM with a replicating HCV infection from phases A to C.
Overall, phase C identified 13 MSM with an incident primary HCV infection, 23 MSM with a prevalent infection because they were not treated during phase B, and 3 MSM who were identified with a prevalent infection by the retrospective assessment of the SHCS database. Of those 39 MSM, 25 (64%) started DAA treatment during phase C and all achieved SVR 12. At the end of phase C, only 14 out of 180 MSM (7%) identified with a replicating infection through the elimination program remained untreated, suggesting a postintervention prevalence of 0.4%.
HCV Incidence
Overall, 34 318 years of observation among 5260 MSM with an active follow-up since 2010 were analyzed. The mean follow-up time per MSM was 6.52 years (interquartile range, 3.75–9.3 years). The number of new HCV infections and reinfections is depicted in Figure 3. Between 2014 and 2019, we observed a decline in the incidence rate of incident primary HCV infections from .49/100 py (95% CI, .3–.78) in 2014 to .12/100 py (95% CI, .03–.5) by the end of October 2019 (data from November to December not yet available). Similarly, the incidence rate of HCV reinfections declined from 2.86/100 py (95% CI, .71–11.4) in 2014 to zero by the end of October 2019. Prior to phase A (2014), the combined HCV incidence was .53/100 py (95% CI, .34–.83) and declined to .12/100 py (95% CI, .03–.48) by the end of October 2019, reflecting a 77% decrease in new infections.
Incidence rate of HCV infection stratified by year and by trial phase A to C. The 3 trial phases took place from October 2015 to June 2016 (phase A), June 2016 to February 2017 (phase B), and March 2017 to November 2017 (phase C). Universal access to direct-acting HCV agents was available in Switzerland from October 2017. The solid circles indicate the incidence rate per 100 patient-years of new HCV infections with the corresponding 95% CIs, whereas the open circles indicate the incidence rate per 100 patient-years of reinfections with the corresponding 95% CIs. For 2019, data were available for the first 10 months until the end of October 2019. A, Primary HCV infections. B, HCV reinfection. C, Primary HCV infections and HCV reinfections combined. Abbreviations: CI, confidence interval; HCV, hepatitis C virus.
Phylogenetic Analysis of Incident HCV Infections
In order to classify incident HCV infections as either domestically acquired or acquired abroad, we sequenced 6 out of the 8 incident genotype 1a infections identified during phase C. In 2 cases, the strains could not be sequenced because of technical reasons. We restricted the analysis to genotype 1a infections because this is the most prevalent genotype among MSM living with HIV in the Western world. Of the 6 sequences, 2 were located in clusters consisting of predominantly Swiss and German sequences. The remaining 4 sequences were classified as corresponding to international transmissions.
DISCUSSION
We conducted the Swiss HCVree Trial to test the concept of HCV micro-elimination among MSM living with HIV in Switzerland. Our elimination program led to a 57% and 84% decrease in incident and prevalent HCV infections, respectively, within 2 years (Figure 2). Similarly, we observed a 77% decline in the HCV incidence rate (Figure 3). However, the effect of our elimination program on the incidence rate was delayed, with the most pronounced decline observed in 2019. The overall prevalence of replicating HCV infections dropped from 4.3% prior to the intervention to 0.4% after the intervention. With this effort, we outperformed the WHO HCV elimination goals for 2020 among this subpopulation and laid the groundwork to achieve the elimination goals for 2030. Our study can serve as a model for other countries, which are aiming to achieve the WHO elimination targets.
Our HCV elimination program is the first to systematically assess the feasibility of a test, treat, and cure HCV micro-elimination program among MSM living with HIV. Novel compared with other studies, we systematically screened MSM for HCV-RNA to detect HCV infections at the earliest stage and repeated RNA-based screening after universal DAA treatment among those identified with a replicating infection. We showed that this approach was feasible and resulted in a more than 50% decline in the incidence rate of HCV infections by the end of 2018 and a 10-fold decrease in the point prevalence of replicating HCV infections. Other successful HCV micro-elimination programs focussing on people living with HIV coinfected with HCV have been recently reported from Australia, the Netherlands, and the United Kingdom [15–18]. In the Australia Control and Elimination within AuStralia of HEpatitis C from people living with HIV (CEASE) study, following universal access to HCV DAA treatment, the HCV viremic prevalence dropped from 82% in 2014 to 8% in 2018 [17]. In a retrospective cohort study conducted at 3 London HIV clinics, a 74% reduction in incident primary infections occurred in MSM living with HIV, coinciding with wider access to DAA-based therapy across London [18]. Finally, in the Dutch Athena cohort, the incidence of new HCV infections decreased by more than 50% after unrestricted access to HCV treatment [16]. This study was not prospectively planned as an elimination program and did not use a systematic test-and-treat approach. These examples show that an increase in diagnosis and treatment rates can lead to substantial achievements towards HCV elimination.
Our study shows the potential but also the challenges of HCV elimination programs. Despite massive efforts within a representative cohort in a resource-rich country, we were still unable to screen a considerable number of MSM in both phases A and C. This is because some physicians decided not to screen their patients within the trial. A reason for that might be the physician’s assumption of a low-risk level for HCV infection in their patients. This hypothesis is supported by the fact that more than 94% of MSM with a missed HCV screening had a negative HCV test recorded in the SHCS database following the trial. The background SHCS database with its high-quality data and systematic collection of clinical parameters allowed us to retrieve these data, test stored samples retrospectively, and to close the gap of missing information. Hence, the implementation and evaluation of an HCV elimination program without having a comprehensive background cohort should be considered with caution.
Our study is unique with regard to its systematic approach with a pre- and postinterventional HCV-RNA–based screening coupled with a tight treatment program. Another strength is that we offered HCV-RNA–based screening to all MSM living with HIV within the SHCS. As shown in our study, one-third of patients with an incident HCV infection had a negative HCV antibody test despite HCV replication [19]. We calculated a median delay of 197 days in the diagnosis of incident HCV infection when following the SHCS standard-of-care annual HCV antibody testing [9]. In the context of an elimination program, such a delay could be relevant because a timely diagnosis and, most importantly, immediate treatment initiation are crucial to avoid new HCV transmission to partners [20–22].
Although we did our best to prevent new HCV infections during the trial, we still identified incident infections after the intervention. For a small number of incident infections we were able to perform phylogenetic analyses, indicating an international transmission network as the source in most cases. With this in mind, HCV elimination programs will probably fail without established systematic rescreening if such a large fraction of infections is acquired abroad [20]. Therefore, a concerted international effort will be needed in order to eliminate this epidemic in the long run. In addition, other public health strategies, such as harm-reduction measures for MSM who inject drugs, are needed.
A limitation—but at the same time also a strength of our program—is that our intervention was limited to MSM living with HIV from the SHCS. With this approach, the generalizability of our findings to other risk groups is limited and HCV infections occurring outside of the SHCS were missed. However, we estimate that 84% of all MSM living with HIV in Switzerland are followed in the SHCS [23]; thus, our study population is highly representative and includes the key population regarding the new HCV epidemic in a real-life setting. In addition, available data clearly suggest that the HCV transmission in Switzerland is concentrated within MSM living with HIV [11]. This may change in the future because recent studies report the spread of HCV from HIV-seropositive to high-risk HIV-seronegative MSM [24]. HCV transmissions among other risk groups, in particular among PWID, have almost stopped [8, 11, 25]. Finally, a possible limitation is that the incidence analysis is based on rather small numbers; hence, this does need to be interpreted with caution.
In conclusion, our results demonstrate the feasibility of a comprehensive systematic test, treat, and cure HCV micro-elimination program among MSM living with HIV. Our approach could be proposed as a model to reach the WHO targets towards HCV micro-elimination in a setting with necessary resources. The fact that a substantial part of incident HCV infections occurred within international transmission networks shows that phylogenetic analysis is key to understanding the epidemic. Likewise, it emphasizes the need for cross-international efforts to reach the WHO elimination goals. Finally, HCV-RNA–based screening with timely diagnosis and treatment initiation is crucial among high-risk MSM to reduce onward transmission and to contain the HCV epidemic in the long run [22]. Because, if omitted, the spread of HCV in Switzerland will take off again [26].
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Members of the Swiss HIV Cohort Study. K. Aebi-Popp, A. Anagnostopoulos, M. Battegay, E. Bernasconi, J. Böni, D. L. Braun, H. C. Bucher, A. Calmy, M. Cavassini, A. Ciuffi, G. Dollenmaier, M. Egger, L. Elzi, J. Fehr, J. Fellay, H. Furrer, C. A. Fux, H. F. Günthard (President of the SHCS), D. Haerry (deputy of “Positive Council”), B. Hasse, H. H. Hirsch, M. Hoffmann, I. Hösli, M. Huber, C. R. Kahlert (Chairman of the Mother & Child Substudy), L. Kaiser, O. Keiser, T. Klimkait, R. D. Kouyos, H. Kovari, B. Ledergerber, G. Martinetti, B. Martinez de Tejada, C. Marzolini, K. J. Metzner, N. Müller, D. Nicca, P. Paioni, G. Pantaleo, M. Perreau, A. Rauch (Chairman of the Scientific Board), C. Rudin, A. U. Scherrer (Head of Data Center), P. Schmid, R. Speck, M. Stöckle (Chairman of the Clinical and Laboratory Committee), P. Tarr, A. Trkola, P. Vernazza, G. Wandeler, R. Weber, and S. Yerly.
Author contributions. The study was designed by D. L. B., A. R., H. F. G., and J. S. F. Data acquisition was performed by D. L. B., B. H., C. G., P. K.-H., C. S., L. S.-V., A. C., M. F., M. S., C. B., P. S., M. R., J. D., E. B., D. N., J. B., A. R., H. F. G., and J. S. F. Statistical analysis was performed by B. L., H. N., and R. D. K. D. L. B. and J. S. F. supervised the study. D. L. B. wrote the first draft of the manuscript. All investigators contributed to data collection and interpretation of the data, reviewed drafts of the manuscript, and approved the final manuscript.
Acknowledgments. The authors are grateful to all patients who participated in the study. They thank all SHCS-affiliated private physicians and all study nurses for their dedicated patient work. They also thank all clinical and laboratory staff at the different SHCS sites who have contributed to this study. The authors highly acknowledge Erik Mossdorf, Silvana Renner, Lital Young, Daniele Viviani, Manfred Bögli, and the team from Merck, Sharp & Dohme AG for supporting the study. They thank the Institute for Medical Virology from the University of Zurich and all the SHCS-affiliated laboratories for their excellent laboratory work; Maja Müller and Alexandra Matter from the Clinical Trials Center Zurich for her great assistance and careful study monitoring; Alexandra Scherrer, Susanne Wild, and Anna Traytel from the data center for excellent data management; Danièle Perraudin and Marianne Amstutz from the SHCS coordination center for their assistance; and Liliane Clausen for the data cleaning. They thank Jenny Crawford for having carefully edited the manuscript. The study protocol and individual participant data that underlie the results reported in this article will be available after de-identification following article publication to investigators whose proposed use of the data has been approved by an independent review committee to achieve aims in the approved proposal. Proposals should be directed to [email protected]; to gain access, data requestors will need to sign a data access agreement.
Disclaimer. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck, Sharp & Dohme AG. Merck, Sharp & Dohme had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Financial support. This study was supported within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant number 177499), by SHCS project #772, and by the SHCS Research Foundation. Additionally, this study was supported by a research grant from the Investigator-Initiated Studies Program of Merck, Sharp & Dohme AG. The data were gathered by the Five Swiss University Hospitals, 2 cantonal hospitals, 15 affiliated hospitals, and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers). This work was further supported by the University of Zurich’s Clinical Research Priority Program viral disease, Zurich Primary HIV infection study (to H. F. G.). R. D. K. is supported by the Swiss National Science Foundation (grant numbers PZ00P3–142411 and BSSGI0_155851).
Potential conflicts of interest. B. L. reports payment for statistical analyses from University Hospital Zurich, during the conduct of the study, and personal fees from Gilead, ViiV, and Janssen, outside the submitted work. P. K.-H. reports grants from ViiV, Janssen, Astellas, and Merck, and nonfinancial support from Gilead, outside the submitted work. H. F. G. reports grants from the Swiss National Science Foundation and Yvonne Jacob Foundation, outside the submitted work. H. F. G. was also an advisor/consultant for ViiV, Gilead, Merck, and a data and safety monitoring board member for Merck, and has received unrestricted research grants from Gilead and Roche. A. R. reports support to his institution for advisory boards and/or travel grants from MSD, Gilead Sciences, Pfizer, and AbbVie, and an investigator-initiated trial grant from Gilead Sciences. All remuneration went to his home institution and not to A. R. personally, and all remuneration was provided outside the submitted work. M. R. reports payments for FibroScan renting for fibrosis-stage assessment, October 2017 (CAAP Arve, Fondation Phenix, Champ-Dollon). M. R. did not receive direct payment. J. S. F. reports grants from ViiV Healthcare and PaxVax, outside the submitted work. R. D. K. reports grants from the Swiss National Science Foundation and personal fees from Gilead Sciences, outside the submitted work. B. H. reports personal fees for a Stakeholder Workshop from MSD, nonfinancial support from Gilead for medication to the PrEp Program, financial support for Campagne/Community work from ViiV, Community health work/Campagne from Gilead, and a SwissPrEPared grant from MSD, outside the submitted work. M. S. reports an Advisory Board Membership paid to his institution from MSD, Gilead, ViiV, Mepha, Sandoz, and Janssen-Cilag, and conference participation from MSD and Gilead, outside the submitted work. E. B. reports fees to his institution for participation on advisory boards and travel grants from Gilead Sciences, MSD, ViiV Healthcare, AbbVie, Sandoz AG, and Pfizer AG, outside the submitted work. D. L. B. reports advisory board fees from ViiV, Gilead, and Merck, and travel grants from Gilead and Merck, during the conduct of the study; and grants from University of Zurich’s Clinical Research Priority Program (CRPP) Viral Infectious Diseases, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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