Little is known about the engagement in hepatitis C virus (HCV) care and completion of HCV treatment in people living with human immunodeficiency virus (HIV) (PLWH) who have HCV coinfection in the Asia-Pacific region. Examining the HCV care cascade can identify barriers to the completion of HCV treatment and facilitate achievement of HCV micro-elimination in PLWH.

To investigate the care cascade of incident HCV infections among PLWH in Taiwan.

PLWH with incident HCV infections, defined as HCV seroconversion, were retrospectively identified by sequential anti-HCV testing of all archived blood samples at National Taiwan University Hospital between 2011 and 2018. All PLWH with incident HCV infections were followed until December 31, 2019. The care cascade of HCV examined included all incident HCV-infected patients, the percentages of anti-HCV antibodies detected by HIV-treating physicians in clinical care, plasma HCV RNA load tested, HCV RNA positivity diagnosed, referral to treatment assessment made, anti-HCV treatment initiated, and sustained virologic response achieved. Those who had HCV seroconversion during the interferon (IFN) era (2011–2016) and the direct-acting antiviral (DAA) era (2017–2018) were analyzed separately. The duration of HCV viremia—from the date of seroconversion to viral clearance by treatments or until the end of observation—and the incidence of sexually transmitted infections (STIs) during the HCV viremic period were estimated.

During the study period, 287 of 3495 (8.2%) PLWH (92.3% being men who have sex with men) who were HCV-seronegative at baseline developed HCV seroconversion by retrospective testing of all archived blood samples. Of the 287 incident HCV infections, 277 (96.5%) had anti-HCV antibodies detected by HIV-treating physicians, 270 (94.1%) had plasma HCV RNA determined and 251 (87.5%) tested positive for HCV RNA. Of those with HCV viremia, 226 (78.7%) were referred to treatment assessment, 215 (74.9%) initiated anti-HCV treatment, and 202 (70.4%) achieved viral clearance. Compared with that in the IFN era, the median interval from HCV seroconversion by retrospective testing to detection of HCV seropositivity by HIV-treating physicians was significantly shorter in the DAA era {179 d [interquartile range (IQR) 87-434] vs 92 d (IQR 57-173); P < 0.001}. The incidence rate of STIs in the DAA vs the IFN era was 50.5 per 100 person-years of follow-up (PYFU) and 38.5 per 100 PYFU, respectively, with an incidence rate ratio of 1.31 (95% confidence interval 0.96-1.77), while the duration of HCV viremia was 380 d (IQR 274-554) and 735 d (IQR 391-1447) (P < 0.001), respectively.

While anti-HCV therapies are effective in achieving viral clearance, our study suggests more efforts are needed to expedite the linkage of PLWH diagnosed with incident HCV infections to HCV treatment.

Viral hepatitis is a major public health threat and approximately 2.3 million people living with human immunodeficiency virus (HIV) (PLWH) are coinfected with hepatitis C virus (HCV) globally[1-3]. Injection drug users (IDUs) have been the major contributors to HCV transmission[4]. In Asia-Pacific region, the prevalence of HCV coinfection among PLWH ranges from 3.8% to 42.6%, and may be as high as 80.8% to 98.5% among IDUs[5,6]. Since 2000, incident HCV infections among PLWH who are MSM have continued to increase in the United States, European countries, and Australia[7-9]. Similar increasing trends were observed among PLWH who are MSM in Asia-Pacific region[10,11]. The causes of the increases of HCV transmission among MSM are multifactorial and are related to concurrent sexually transmitted infections (STIs), unprotected anal intercourse, traumatic sexual contacts, and use of recreational drugs by inhalation or injection[12].

The evolution of HCV treatment from interferon (IFN)-based therapy to IFN-free direct-acting antivirals (DAAs) has significantly improved tolerability and effectiveness in achieving viral clearance[13]. The rates of viral clearance with DAAs are similarly high for HCV-monoinfected patients and HCV/HIV-coinfected patients in clinical trials and real-world experience[14-18]. With the introduction of effective DAAs, ending the HCV epidemic is considered an achievable goal by scaling up diagnosis and treatment of HCV infection[1]. Among the interventional strategies proposed to achieve hepatitis elimination, the continuum assessed by the "cascade of care" on the population level is suggested to evaluate the status of hepatitis treatment services and the level of engagement in care[19,20]. The proportion of patients in each step of the cascade—infected, tested, status confirmed, engagement in care, treatment initiated, cured, and followed up for chronic care—reflects the coverage of diagnosis, access to treatment, and quality of care.

In Taiwan, pegylated IFN plus ribavirin (PEG-IFN/RBV) has become the standard anti-HCV treatment regimen since 2004 and has been fully reimbursed by the National Health Insurance (NHI) since 2009[21,22]. DAAs were not available until 2017, when the regimens were restricted to individuals with chronic HCV infection with evidence of significant hepatic fibrosis. Generic versions of patented DAAs could be purchased for individual use from Bangladesh[23]. Before 2019, referral to a hepatologist for hepatitis C evaluation and treatment was required according to NHI regulations. The reimbursement restrictions on the use of DAAs were lifted in January of 2019 by allowing HCV viremic patients to initiate DAAs regardless of liver fibrosis status. Subsequently, PLWH with HCV viremia could be evaluated and DAAs initiated by HIV-treating physicians at infectious disease clinics.

In this study, we aimed to examine the HCV care cascade among PLWH who received a diagnosis of incident HCV infection at a university hospital in Taiwan.

Between January 2011 and December 2018, 3,495 PLWH had a negative anti-HCV antibody test at baseline (Figure 1) and HCV seroconversion was detected in 294 (8.4%) PLWH. After excluding 7 PLWH who were lost to follow-up when seroconversion occurred, a total of 287 PLWH were included in the analysis of the HCV care cascade.

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Figure 1 Patient flow. Between 2011 and 2018, 3495 people living with human immunodeficiency virus (HIV) (PLWH) had negative anti-hepatitis C virus (HCV) antibody tests at baseline and HCV seroconversion was detected in 294 (8.4%) PLWH. After excluding 7 PLWH who were lost to follow-up when HCV seroconversion occurred, a total of 287 PLWH were included in the analysis of the care cascade of incident HCV infections. HIV: Human immunodeficiency virus; NTUH: National Taiwan University Hospital; HCV: Hepatitis C virus.

The clinical characteristics of the included 287 PLWH with recently acquired HCV infection are shown in Table 1. All of them were male, with a mean age of 34.5 years [standard deviation (SD) 7.6]. The mean PVL was 1.72 log₁₀ copies/mL (SD 1.09) and mean CD4 count was 597.7 cells/mm³ (SD 251.1) at the time of HCV seroconversion. The HBsAg seropositivity rate was 14.9% and active or previous syphilis was present in 89.2%. The risk groups of HIV acquisition included 265 (92.3%) MSM, 5 (1.8%) heterosexuals, 4 (1.4%) IDUs, and 13 (4.5%) unknown. The mean plasma HCV RNA load was 5.72 log₁₀ copies/mL (SD 1.50). Twenty-two (7.7%), 84 (29.3%), 119 (41.5%), 6 (2.1%), and 34 (11.8%) PLWH had infection with HCV genotypes 1a, 1b, 2a, 3, and 6, respectively, and 3 (1%) had mixed infections of genotypes 1b and 2.

Of the 287 PLWH, 277 (96.5%) were found to have HCV seroconversions by HIV-treating physicians, including 8 diagnosed at the stage of acute infection with positive HCV RNA and negative anti-HCV antibody. Plasma HCV RNA load was determined in 270 (94.1%) PLWH after seroconversion, with 19 (12.5%) clearing viremia spontaneously and 251 (87.5%) remaining viremic (Table 2). Overall, 226 (78.7%) PLWH were referred to hepatology clinics for treatment assessment, and anti-HCV treatments were initiated in 215 (74.9%) PLWH, of whom 202 (70.4%) achieved SVR (Table 2).

Compared with PLWH who had HCV seroconversion in the IFN era (2011–2016), those who seroconverted in the DAA era (2017–2018) had higher achievement rates of all sequential steps of the care cascade (Figure 2), though not reaching statistical significance. The rate of antibody diagnosis within one year of HCV seroconversion was significantly higher in the DAA era than that in the IFN era (88.2% vs 69.5%; P < 0.001) (Figure 2). In the IFN era, the major gap of engagement in care was from HCV RNA positivity to referral for assessment and treatment, which resulted in a loss of 11.8% of those found to be HCV viremic.

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Figure 2 Care cascade of incident hepatitis C virus infections in the interferon and direct-acting antiviral eras. In the interferon era (blue columns), 176 people living with human immunodeficiency virus (HIV) (PLWH) had incident hepatitis C virus (HCV) infections by retrospective testing of all archive blood samples; 167 (94.9%) were found to have HCV seroconversion by HIV-treating physicians; and the diagnostic rate within one year after seroconversion was 69.4% (116 out of 167). Plasma HCV RNA was tested in 162 (97.0%) PLWH after seroconversion, of which 152 (93.8%) were viremic. A total of 134 (88.2%) viremic PLWH were referred to hepatology clinics; anti-HCV treatments were initiated in 131 (97.8%), and 120 (91.6% of all treated PLWH) achieved sustained virologic response (SVR). In the direct-acting antiviral era (orange columns), 111 PLWH had incident HCV infections; 110 (99.1%) were found to have HCV seroconversion by HIV-treating physicians; and the diagnostic rate within one year after seroconversion was 88.2% (97 out of 110). Plasma HCV RNA was detected in 108 (98.2%) PLWH after seroconversion and 99 (91.7%) were viremic. A total of 92 (92.9%) viremic PLWH received treatment assessment, anti-HCV treatments were initiated in 84 (91.3%), and 82 (97.6% of all treated patients) achieved SVR. IFN: Interferon; DAA: Direct-acting antiviral; HCV: Hepatitis C virus; PLWH: People living with human immunodeficiency virus.

The median interval from seroconversion to detection of HCV seropositivity by HIV-treating physicians was 130 d [interquartile range (IQR), 80-295], which was significantly shorter in the DAA era than in the IFN era [92 d (IQR, 57-173) vs 179 d (IQR 87-434); P < 0.001] (Table 2, Figure 3). From detection of HCV seropositivity to HCV RNA testing, the interval was 21 d (IQR 6-39) and 12 d (IQR 6-68) in the IFN and DAA eras, respectively (P = 0.19). The intervals from HCV RNA testing to treatment assessment and from assessment to treatment initiation were longer in the DAA era compared with those in the IFN era, 81 d (IQR 14-169) vs 26 d (IQR 7-208), and 42 d (IQR 18-84) vs 35 d (IQR 27-90), which were not statistically significantly different (P = 0.25 and P = 0.55, respectively). The duration of viremia was 735 d (IQR 391-1447) in the IFN era, which was significantly longer than that in the DAA era (380 d; IQR 274-554; P < 0.001).

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Figure 3 Intervals between steps of the care cascade of incident hepatitis C virus infections. A: Demonstration of the intervals between each step of the care cascade; B: In all included people living with human immunodeficiency virus (HIV) (PLWH), the median interval from seroconversion to detection of hepatitis C virus (HCV) seropositivity by HIV-treating physicians was 130 days, which was significantly shorter in the direct-acting antiviral (DAA) era (median 92 d) than that in the interferon (IFN) era (median 179 d) (P < 0.001). In the IFN era, the median interval from detection of HCV seropositivity to HCV RNA testing was 21 d, that from RNA testing to referral to treatment assessment was 26 d, and that from assessment to treatment initiation was 35 d. In the DAA era, the median interval from detection of HCV seropositivity to HCV RNA testing was 12 d, that from RNA testing to referral to treatment assessment was 81 d, and that from assessment to treatment initiation was 42 d. The differences in the intervals after antibody diagnosis were not statistically significant between PLWH included in the IFN era and those in the DAA era. HCV: Hepatitis C virus; IFN: Interferon; DAA: Direct-acting antiviral.

Among the HCV seroconverters in the IFN era, a total of 165 episodes of STIs were observed in the entire HCV viremic duration of 428.2 PYFU, resulting in an incidence rate of 38.5 per 100 PYFU. In the DAA era, the HCV seroconverters acquired a total of 55 episodes of STIs during 108.8 PYFU of viremia, leading to an incidence rate of 50.5 per 100 PYFU. The incidence rate ratio (IRR) of STIs in the DAA era vs the IFN era was 1.31 (95%CI 0.96-1.77).

Figure 4 demonstrates the breakdown of HCV treatment uptake by year. The annual number of PLWH with HCV viremia who received IFN-based therapy was unchanged from 2012 to 2016. With the introduction of DAAs in 2016, the number of PLWH receiving DAA treatment increased year by year, especially in 2019, when restrictions on DAA reimbursement were lifted and all HCV viremic patients could be treated with DAAs.

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Figure 4 Hepatitis C virus treatment uptake by year from 2011 to 2019. The annual numbers of people living with human immunodeficiency virus (PLWH) who received interferon-based therapy were unchanged from 2012 to 2016. With the introduction of direct-acting antivirals (DAAs) since 2016, the number of PLWH receiving DAAs increased annually, especially in 2019, when the restrictions on the DAA reimbursement were lifted and all hepatitis C virus viremic patients could be treated with DAAs. DAA: Direct-acting antiviral; IFN: Interferon.

In this study, we observed high rates of linkage to HCV care and retention in the care system among PLWH at our institution, in both the IFN and DAA eras. The retention rates between each step of the care cascade after detection of incident HCV infection primarily exceeded 90% (Figure 2). A major barrier noted in the IFN era was referral to treatment assessment (88.2%) after detection of HCV viremia, while this gap seemed diminished in the DAA era. In addition, the duration of HCV viremia, from seroconversion to completion of HCV treatment, was markedly shortened in the DAA era compared to that in the IFN era (380 d vs 735 d; P < 0.001). The improvement was mainly due to early diagnosis of recently acquired HCV infection by HIV-treating physicians because the diagnostic rate within one year after seroconversion increased from 69.5% (116/167) to 88.2% (97/110), and the median time from seroconversion to antibody diagnosis was shortened from 179 d to 92 d (P < 0.001).

The occurrence of STIs during HCV viremia represented risky sexual behavior, potentially resulting in onward transmission of HCV to their contacts. The incidence rate of STIs observed in the DAA era was higher than that in the IFN era, though not reaching statistical significance (50.5 vs 38.5 per 100 PYFU; IRR 1.31, 95%CI 0.96-1.77). In contrast, the total number of STI episodes was far fewer in the DAA era vs the IFN era (55 episodes among 111 patients vs 165 episodes among 176 patients, respectively), likely due to a shorter duration of HCV viremia. The curtailing of HCV viremia with the initiation of effective DAAs may indicate reduced opportunities to transmit HCV during the viremic period.

There are limited data to describe the care cascade after incident HCV infections were diagnosed both in the general population and in HCV-coinfected PLWH in the Asia-Pacific region. In our study, we tested archived blood samples to include all patients who had recent HCV infections in the previous year and estimated the time of seroconversion. In doing so, we could assess the rate of antibody diagnosis of HCV infection by treating physicians, the interval of delay in clinical diagnosis, and the duration of HCV viremia before effective anti-HCV treatments were initiated. Prior population-level studies of the care cascade either estimated the seroprevalence of HCV[24,25] or described the cascade since the diagnosis of anti-HCV positivity[26]. In single-center studies focusing on HCV-coinfected PLWH, the actual numbers of HCV infections were not shown in the care cascade[27,28].

Previous population-based care cascade assessments for HCV infection in the IFN era revealed low rates of retention in care and treatment initiation, probably related to concerns about inconvenience, lower effectiveness, intolerability, and higher rates of adverse effects with IFN/RBV treatment. The antibody diagnostic rate was 50% to 75%; HCV RNA testing was performed in 30 to 50% of patients; less than 20% of patients received HCV treatment; and the final SVR rate was lower than 10%[24,25]. At our institution during the IFN era, the antibody diagnosis, HCV RNA testing, treatment initiation, and SVR rates were 94.9%, 92.0%, 74.4%, and 68.2%, respectively, much higher than those of previous population-level studies. We believe that regularly scheduled follow-up visits for fully-reimbursed HIV antiretroviral treatments in the majority of PLWH might have provided an opportunity to facilitate HCV testing and increase engagement of HCV care[29,30]. However, mandatory referrals to a hepatologist for HCV pretreatment assessment and management may have raised the barrier to anti-HCV treatment initiation and achievement of viral clearance, as such a requirement negatively impacts convenience and costs, thereby potentially increasing the risk of dropout from HCV care. This barrier has diminished since 2019 when NHI approved HIV-treating physicians to participate in HCV assessment and treatment for PLWH at infectious disease clinics. The rate of treatment assessment after HCV RNA positivity increased from 88.2% (134/152) in the IFN era to 92.9% (92/99) in the DAA era.

The introduction of DAAs has been shown to improve engagement of HCV care and treatment uptake. The British Columbia Hepatitis Tester Cohort demonstrated improvement of the care cascade in the DAA era. Of the patients who tested anti-HCV-positive, 83% had HCV RNA testing done; and, of those who were HCV viremic and were genotyped, 61% received DAA therapy, with 90% achieving SVR[31]. In a report from seven HCV elimination studies among PLWH in the early DAA era, the average treatment uptake increased to 48% and treatment completion rates reached 96%[32]. Our current study showed a significantly higher rate of linkage to care, with > 90% of PLWH consistently advancing from each cascade step to the next in the DAA era, which resulted in a total of 84.8% (84/99) viremic patients initiating anti-HCV treatments, and 97.6% (82/84) achieving SVR. In the Swiss HIV Cohort Study, the treatment incidence increased from 4.5 per 100 PYFU before the availability of DAAs, to 22.4 per 100 PYFU after the introduction of second-generation DAAs[33]. These findings were in line with observations from our study. While the annual number of IFN-based therapy remained unchanged from 2012 to 2016, the number of DAA treatment initiated progressively increased from 2016 to 2018, which further rocketed in 2019, when the restriction on DAA reimbursement was lifted (Figure 4). During the period between 2016 and 2018, when access to DAA through NHI reimbursement remained limited, generic DAAs could be purchased overseas by PLWH themselves; however, accessibility was limited by the cost incurred. During this period, we found that the median intervals from HCV RNA testing to referral to treatment assessment, and those from referral to treatment initiation were longer than those in the IFN era, though not reaching statistical significance (Table 2 and Figure 3).

There are several limitations in this study. First, the cascade of HCV care from this single-center study might not be generalizable to other institutions in Taiwan, given that discrepancies in the patients’ demographic and clinical characteristics and socio-economic status may exist. At our institution, PLWH with recent HCV infection were mainly MSM, accounting for more than 90% of the included patients, while the percentages of heterosexual and IDUs were both lower than 2%. Prior studies suggested from an assessment of the HCV care cascade in IDUs that active drug users had poorer treatment adherence, resulting in lower rates of viral clearance[34-36]. Second, our study did not investigate factors that may be associated with failure of engagement in the HCV care cascade. Third, HCV reinfection, which can occur in this high-risk group[37-39], were not included in the analyses of the HCV care cascade.

In conclusion, we describe the HCV care cascade at a referral hospital in Taiwan from the IFN era to the DAA era. The rates of engagement in each step of the HCV care cascade were high in both eras and the barriers to referral and reimbursement diminished over time. However, given both the longer intervals of HCV viremia observed in the DAA era and a higher incidence of STIs potentially contributing to onward transmission of HCV, more efforts are needed to expedite the linkage of PLWH diagnosed with incident HCV infections to HCV treatment.

The authors would like to express their gratitude to the staff of National Taiwan University Hospital-Statistical Consulting Unit (NTUH-SCU) for statistical consultation and analyses.