High prevalence of unawareness of HCV infection status among both HCV-seronegative and seropositive people living with human immunodeficiency virus in Taiwan.

OBJECTIVES: HCV infection status awareness is crucial in the HCV care continuum for both HCV-seropositive (HCV-positive status awareness) and seronegative (HCV-negative status awareness) populations. However, trends in the unawareness of HCV infection status (UoHCV) remain unknown in HIV-positive patients. This study investigated UoHCV prevalence, the associated factors of UoHCV, and its association with HCV-related knowledge in HIV-positive patients.
METHODS: For this cross-sectional, multicenter, questionnaire-based study, 844 HIV-infected participants were recruited from three hospitals in Taiwan from June 2018 to March 2020. Participants were grouped by HCV serostatus (HCV-seronegative [n = 734] and HCV-seropositive [n = 110]) and categorized by their HIV diagnosis date (before 2008, 2008-2013, and 2014-2020). Exploratory factor analysis was used to categorize the 15 items of HCV-related knowledge into three domains: route of HCV transmission, HCV course and complications, and HCV treatment.
RESULTS: The prevalence of UoHCV was 58.7%-62.6% and 15.1%-31.3% in the HCV-seronegative and HCV-seropositive groups, respectively, across 3 periods. More participants with UoHCV believed that HCV infection was only contracted by intravenous injection. In the HCV-seropositive group, participants with UoHCV were more likely to have HIV diagnosis before 2008 (vs. 2014-2020), be men who have sex with men (vs. people who inject drugs), and have hepatitis A virus seronegativity. In the HCV-seronegative group, participants with UoHCV were more likely to have a recent history of sexually transmitted diseases, but had a lower education level, had received less information on HCV infection from clinicians, and were less likely to have heard of HCV infection prior to the research. UoHCV was associated with lower scores for three domains of HCV-related knowledge in both groups.
CONCLUSIONS: The negative association of UoHCV with HCV-related knowledge suggests that strategies targeting patients according to their HCV serostatus should be implemented to reduce UoHCV and eradicate HCV infection among HIV-positive patients.

Introduction

The global seroprevalence of the hepatitis C virus (HCV) is approximately 2.5% [1]. Although treatment with direct-acting antivirals (DAAs) can lead to the elimination of HCV viremia and a curative outcome in more than 90% of patients with chronic HCV infection [2], several barriers to eradicating HCV infection still exist, including the high costs of drugs [3], frequent loss to follow-up after diagnosis [4], high rate of early HCV reinfection among patients who have recently received drug injections [5], and ongoing high-risk behaviors associated with HCV infection (even after clearance of HCV infection) [6]. The identification of undiagnosed patients, timely provision of DAAs to HCV-seropositive populations [7, 8], and the prevention of transmission among at-risk HCV-seronegative populations must be prioritized to eliminate HCV infection [7].

Awareness of HCV infection status is crucial for both HCV- seropositive and HCV-seronegative populations. Although the short- and long-term impacts of HCV-positive status awareness among HCV-seropositive patients on their risk behavior remain matters of debate [9-12], HCV-positive status awareness is essential in the HCV care continuum in terms of treatment eligibility and taking medical advice on viral transmission [12, 13]. However, unawareness of HCV infection status (UoHCV) remains common in the HCV-seropositive population, with prevalence rates of 20.5% in Italy [14], 16.6%–35.1% in Taiwan [15-17], and 14%–51% in the United States [18, 19]. In the HCV-seronegative population at risk of contracting HCV, people who inject drugs (PWID) may engage in high-risk behaviors (e.g., sharing a syringe or injecting themselves with drugs) less frequently if they are aware of their HCV infection status (i.e., HCV-negative status awareness) [9, 12]. However, a nationwide screening program in Taiwan revealed a 33% prevalence of UoHCV in the HCV-seronegative population [16].

People living with human immunodeficiency virus (HIV) infection (PLWH) are at risk of HCV infection because the transmission routes of HCV infection, such as unprotected sex and drug injection, are similar to those of HIV infection [6, 20, 21]. Moreover, individuals coinfected with HCV and HIV are less likely to seek HCV care [22-24], which may contribute to a significantly decreased quality of life and quicker progression of liver disease, especially in those who are homeless or marginally housed [25]. Additionally, patients with HCV/HIV coinfection have higher rates of death and disease progression, including the progression of histological fibrosis/cirrhosis and decompensated liver disease, than do patients with HCV monoinfection [26]. Therefore, HCV screening, treatment, and prevention strategies should be strictly implemented among PLWH [27]. However, although strategies have been implemented worldwide to combat the spread of HCV, no study has explored the prevalence or associated factors of UoHCV among PLWH [11]. Serostatus awareness facilitates the next step in the continuum of HCV care, namely providing affected patients with access to health care, relevant consultation, and potential treatment, which are necessary to eradicate HCV. Furthermore, knowledge regarding HCV infection is essential for the further utilization of HCV treatment [28, 29]. In one study, the majority of participants had limited knowledge regarding the complications of chronic HCV infection despite being aware of the high prevalence of HCV among men who have sex with men (MSM) [30]. However, little is known regarding the association of UoHCV with knowledge of HCV among PLWH. We hypothesized that UoHCV is negatively associated with an individual’s HCV-related knowledge, regardless of their HCV serostatus.

We conducted a cross-sectional questionnaire-based study at three HIV referral centers in Taiwan from June 2018 to March 2020. We evaluated the prevalence of UoHCV, explored the determinants of UoHCV, and evaluated the associations of UoHCV with different domains of HCV-related knowledge (i.e., route of HCV transmission, HCV course and complications, and HCV treatment) among a sample of PLWH stratified by HCV serostatus.

Materials and methods

Study design and setting

This cross-sectional, multicenter, questionnaire-based study was conducted from June 1, 2018, to March 31, 2020, at Kaohsiung Municipal Siaogang Hospital and Kaohsiung Municipal Ta-Tung Hospital, which are regional hospitals in southern Taiwan, and at Kaohsiung Medical University Hospital, which is the largest referral center for PLWH in southern Taiwan. The HCV seropositivity in southern Taiwan is 8.6% [31], which is higher than that in northern Taiwan (1.2%–2.7%) [32].

Development of the study questionnaire

A questionnaire was designed to investigate participants’ awareness of HCV infection status, knowledge of different aspects of the disease, perceived risk of HCV infection, and assessment of potential exposure to HCV.

An expert group comprising an HIV case manager, HIV specialists, hepatologists, and researchers developed the preliminary questionnaire used in this study. The preliminary questionnaire was then modified based on feedback from 30 PLWH after they had completed a pretest. The questionnaire was tested again with 20 PLWH and further modified. Because of the lack of a standardized scoring system for evaluating different categories of HCV-related knowledge, the questionnaire items were modified after a review of pertinent studies [28–30, 33]. The section on the perceived risk of HCV infection was also modified [34].

The final questionnaire comprised variables in the following five categories: sociodemographic characteristics, awareness of HCV infection status, knowledge of HCV infection, perceived risk of HCV infection, and assessment of potential exposure to HCV (S1 File). Participants were instructed to answer the 15 HCV-related knowledge items by providing one of the following responses: “yes,” “no,” or “I do not know” [35]. One point was awarded for each correct response, and no point was awarded for incorrect or “I do not know” responses. Therefore, the mean scale scores ranged from 0 to 1, with higher scores indicating greater HCV-related knowledge. Variables correlated with the respondents’ perceived risk of HCV infection were measured on a 5-point Likert scale (strongly disagree, disagree, neither agree nor disagree, agree, and strongly agree).

Participants and study procedure

Two trained investigators screened PLWH by reviewing their available medical records at the participating hospitals for the period from January 1, 2000, to March 31, 2020. Patients who were less than 20 years old during the screening period (June 1, 2018, to March 31, 2020), had not undergone HCV antibody tests within 1 year before enrollment, or were lost to follow-up during the screening period were excluded. The participants completed the questionnaires on Google Forms.

The participants were classified into one of two groups according to their HCV serostatus: a HCV-seronegative group and a HCV-seropositive group. They were then stratified according to their awareness of their HCV infection status. Finally, each of the two groups was further divided into two subgroups: the unawareness/HCV-seronegative (subgroup 1), awareness/HCV-seronegative (subgroup 2), unawareness/HCV-seropositive (subgroup 3), and awareness/HCV-seropositive (subgroup 4).

The study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-SV(I)-20180024) and adhered to the principles of the Declaration of Helsinki. The investigators obtained signed informed consent forms from all patients before enrollment.

Definitions

The participants were categorized by three distinct periods based on the calendar year of their first confirmed HIV diagnosis: before 2008 (period 1, before the remission of the HIV epidemic among PWID) [36], 2008–2013 (period 2, remission of the HIV epidemic among PWID but before the introduction of oral DAAs), and 2014–2020 (period 3, after the introduction of oral DAAs).

In this study, awareness of HCV infection status was defined as participants’ self-reported recognition of their HCV infection status at the time of enrollment in the study (i.e., HCV-seropositive patients’ awareness of their HCV-positive status and HCV-seronegative patients’ awareness of their HCV-negative status), whereas UoHCV was defined as participants’ self-reported unawareness of their HCV infection status [8, 16].

The behavioral indicators of a high risk of exposure to HCV infection were modified from other studies and included using any intravenous recreational drugs [12], engaging in chemosexual behaviors within the preceding 6 months [37], having a sexual partner within the preceding 6 months (assessment options were no sexual partners, one regular sexual partner, no regular sexual partners/less than five partners, and no regular sexual partner/more than five partners) [37], and engaging in other activities involving sexual contact within the preceding 6 months [37].

Outcomes of interest

The primary outcome of interest was the prevalence of UoHCV across the three study periods, stratified by the participants’ HCV serostatus. Secondary outcomes were factors associated with UoHCV and the associations of UoHCV with the mean scores for three domains of HCV knowledge (route of HCV transmission, HCV course and complications, and HCV treatment) among the participants stratified by their HCV serostatus.

Statistical analysis

Descriptive analyses were performed on the characteristics of the participants in the four subgroups. The categorical and continuous variables in each subgroup were compared through χ2 tests (or Fisher’s exact tests) and independent t tests, respectively. The prevalence of UoHCV was defined as the proportion of participants with UoHCV at the time of questionnaire completion. The trend analyses of the prevalence of UoHCV stratified by HCV serostatus in the three periods were performed using a Cochran–Armitage trend test with modified ridit scores.

Backward stepwise binary logistic regressions were performed to calculate odds ratios and evaluate associations in the bivariate and multivariable analyses between surveyed factors and UoHCV among all the participants and among those in the two HCV serostatus groups. To simultaneously consider the effects of all variables in the multivariable model, we adopted a backward approach.

To determine the validity of the 15 items used to measure the participants’ knowledge regarding HCV infection, an item analysis was performed for the assessment of item discrimination. We also performed exploratory factor analysis by using principal axis factoring with varimax rotation to investigate the structural domain of the 15 items, and three domains were finally categorized: route of HCV transmission (domain 1), HCV course and complications (domain 2), and HCV treatment (domain 3). Cronbach’s α was used to measure the internal consistency of the items in each structural domain, where α represented the function of the number of items in a test. Cronbach’s α ≥ 0.7 indicates high reliability.

Finally, to determine the association of UoHCV with the means of the total and domain-specific scores of HCV-related knowledge, we employed a multilinear regression model with a backward approach. β along with 95% confidence intervals were calculated to estimate the effects of UoHCV and directions of all associations. A backward approach was also adopted to enable the effects of all the variables to be simultaneously considered in the multivariable model.

All tests were two-tailed, and p < 0.05 was considered significant. Statistical analyses were performed using SPSS Statistics version 25.0 (IBM, Armonk, NY, USA).

Results

Participants

The study flowchart is displayed in Fig 1. Among the 1448 eligible PLWH, 525 were unwilling to participate in the study, and 79 were excluded for incomplete responses to questionnaire items. A total of 844 PLWH were included in the final analysis. They were divided into HCV-seronegative (n = 734) and HCV-seropositive (n = 110) groups. The two groups were further divided into subgroups 1 (unawareness/HCV-seronegative; n = 448), 2 (awareness/HCV-seronegative; n = 286), 3 (unawareness/HCV-seropositive; n = 22), and 4 (awareness/HCV-seropositive; n = 88).

Fig 1

Study flowchart.

Characteristics of the study participants

Table 1 presents the sociodemographic characteristics, laboratory profiles, perceived risk of HCV infection, and high-risk behaviors for HCV infection of the participants in each subgroup. The mean (standard deviation) age at enrollment among all the participants was 36.6 (±9.8) years, and 98.1% of the participants were men. The routes of HIV transmission included men who have sex with men (MSM) (73.5%), bisexual contact (13.0%), heterosexual contact (8.3%), and drug injection (5.2%). Approximately 21.0%, 30.2%, and 48.8% of the participants were diagnosed as having HIV in periods 1, 2, and 3, respectively.

Table 1

Comparison of sociodemographic characteristics of 844 PLWH between those with and without awareness of their HCV infection status, stratified by HCV serostatus.

		All N = 844	HCV-seronegative group		P	HCV-seropositive group		P
			Subgroup 1 (Unawareness)	Subgroup 2 (Awareness)		Subgroup 3 (Unawareness)	Subgroup 4 (Awareness)
			N = 448	N = 286		N = 22	N = 88
Sociodemographic variables
• Period of HIV diagnosis, n (%)					0.621			0.167
	Period 1 (before 2008)	177 (21.0)	75 (16.7)	49 (17.1)		8 (36.4)	45 (51.1)
	Period 2 (2008–2013)	255 (30.2)	135 (30.1)	95 (33.2)		4 (18.2)	21 (23.9)
	Period 3 (2014–2020)	412 (48.8)	238 (53.1)	142 (49.7)		10 (45.5)	22 (25.0)
• Male gender, n (%)		828 (98.1)	443 (98.9)	281 (98.3)	0.471	21 (95.5)	83 (94.3)	>0.999
• Age		36.6 (9.8)	35.3 (9.8)	36.6 (9.3)	0.091	38.3 (10.8)	42.5 (9.4)	0.70
• Education above college level, n (%)		452 (53.6)	226 (50.4)	193 (67.5)	<0.001	7 (31.8)	26 (29.5)	0.835
• Employment, n (%)		690 (81.8)	360 (80.4)	250 (87.4)	0.013	15 (68.2)	65 (73.9)	0.592
• Marriage, n (%)		42 (5.0)	21 (4.7)	13 (4.5)	0.389	2 (9.1)	6 (6.8)	0.403
• HIV diagnosis in Kaoping area, n (%)		762 (90.3)	400 (89.3)	258 (90.2)	0.689	20 (90.9)	84 (95.5)	0.345
• HIV-related risk assessment					0.720			0.023
	MSM	620 (73.5)	339 (75.7)	223 (78.0)		15 (68.2)	43 (48.9)
	Heterosexual	70 (8.3)	42 (9.4)	20 (7.0)		2 (9.1)	6 (6.8)
	Bisexual	110 (13.0)	65 (14.5)	42 (14.7)		2 (9.1)	1 (1.1)
	PWID	44 (5.2)	2 (0.4)	1 (0.3)		3 (13.6)	38 (43.2)
• History of sexually-transmitted diseases within the preceding 6 months, n (%)		150 (17.8)	94 (21.0)	40 (14.0)	0.017	5 (22.7)	11 (12.5)	0.307
• Has your doctor ever provide you the information about your HCV infection status before		369 (43.7)	95 (21.2)	193 (67.5)	<0.001	10 (45.5)	71 (80.7)	0.001
• Have ever heard of HCV		678 (80.3)	299 (66.7)	273 (95.5)	<0.001	18 (81.8)	88 (100.0)	<0.001
Laboratory data at time of questionnaire, n (%)
• HAV Ab seropositivity		538 (64.0)	276 (61.7)	187 (65.6)	0.290	11 (50.0)	64 (74.4)	0.027
• HBs Ag seropositivity		84 (10.0)	45 (10.0)	26 (9.1)	0.681	2 (9.1)	11 (12.6)	0.646
Perceived risk of HCV infection
• Only those who inject medication intravenously can get hepatitis C		2.12 (1.00)	2.3 (1.02)	1.86 (0.88)	<0.001	2.18 (1.30)	2.03 (0.99)	0.558
• The sexual behavior styles that I like put me at risk of hepatitis C infection.		2.95 (1.09)	2.99 (0.99)	2.91 (1.23)	0.347	3.23 (1.11)	2.81 (1.12)	0.118
• I am more worried about hepatitis C virus than HIV		2.90 (1.04)	2.90 (0.97)	2.90 (1.16)	0.952	2.64 (1.00)	3.00 (0.98)	0.125
Assessment of potential exposures to HCV within the preceding 6 months
• Use of intravenous form of recreational drugs, n (%)					0.126			0.215
	No use	756 (89.6)	412 (92.0)	274 (95.8)		18 (81.8)	52 (59.1)
	Yes, less than a year	35 (4.1)	23 (5.1)	5 (1.7)		1 (4.5)	6 (6.8)
	Yes, 1–3 years	20 (2.4)	10 (2.2)	5 (1.7)		1 (4.5)	4 (4.5)
	Yes, more than 3 years	33 (3.9)	3 (0.7)	2 (0.7)		2 (9.1)	26 (29.5)
• Engagement in chemosexual behaviors within the preceding 6 months, n (%)		109 (12.9)	65 (14.5)	34 (11.9)	0.311	5 (22.7)	5 (5.7)	0.013
• Status of having a sexual partner within the preceding 6 months, n (%)					0.383			0.832
	No sexual partner	316 (37.4)	164 (36.6)	91 (31.8)		12 (54.5)	49 (55.7)
	Regular sexual partner	334 (39.6)	173 (38.6)	125 (43.7)		7 (31.8)	29 (33.0)
	No regular sexual partners, less than 5 partners	144 (17.1)	79 (17.6)	54 (18.9)		3 (13.6)	8 (9.1)
	No regular sexual partner, more than 5 partners	50 (5.9)	32 (7.1)	16 (5.6)		0 (0.0)	2 (2.3)
• Sexual experiences within the preceding 6 months, n (%)
	Ever experience sadomasochism	23 (2.7)	10 (2.2)	9 (3.1)	0.447	1 (4.5)	3 (3.4)	>0.999
	Ever experience group sex participation	82 (9.7)	50 (11.2)	27 (9.4)	0.458	1 (4.5)	4 (4.5)	>0.999
	Ever experience Insertive/receptive unprotected anal intercourse	440 (52.1)	236 (52.7)	172 (60.1)	0.047	9 (40.9)	23 (26.1)	0.195
	Ever experience vaginal sex	87 (10.3)	42 (9.4)	32 (11.2)	0.426	2 (9.1)	11 (12.5)	>0.999

Abbreviations: Ab, antibody; Ag, antigen; HBs, hepatitis B surface; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PWID, people who inject drugs; MSM, men who have sex with men; PLWH, people living with human immunodeficiency virus.

Trend analysis of the prevalence of UoHCV across the three periods stratified by participants’ HCV serostatus

The prevalence rate of UoHCV was 46.9% in period 1, 54.5% in period 2, and 60.2% in period 3 (p for trend = 0.003; Fig 2). The overall prevalence of UoHCV was 58.7%–62.6% in the HCV-seronegative group (p for trend = 0.497) and 15.1%–31.3% in the HCV-seropositive group (p for trend = 0.086). Participants with a history of treatment for HCV were excluded from the HCV-seropositive group because all of these patients were aware of their HCV infection status and were thus not part of the target population; this exclusion increased the prevalence of UoHCV to 33.8% (ranging from 30.8% in period 1 to 37.0% in period 3, p for trend = 0.632).

Fig 2

Trend analyses of prevalence of UoHCV stratified by HCV serostatus in three periods according to the calendar year of first confirmed HIV diagnosis (period 1 [before 2008], period 2 [2008–2013], and period 3 [2014–2020]).

Prevalence of unawareness of HCV infection status across the three periods among all participants and among HCV-seronegative individuals, HCV-seropositive individuals receiving HCV therapy, and HCV-seropositive individuals not receiving HCV therapy. Cochran–Armitage trend test with modified ridit scores was used to analyze the trends in the prevalence of unawareness of HCV infection status for periods 1 to 3. Abbreviations: HCV, hepatitis C virus.

Factors associated with UoHCV among PLWH stratified by HCV serostatus

After stratification by HCV serostatus, the two groups differed in terms of factors associated with UoHCV in a binary logistic regression (Table 2). In the HCV-seropositive group, the proportion of participants who believed that intravenous injection was a requirement for contracting HCV was greater among individuals with UoHCV than among those who were aware of their HCV status. Furthermore, these individuals with UoHCV were less likely to have received an HIV diagnosis in period 3 (vs. period 1), be PWID (vs. MSM), and have hepatitis A virus (HAV) seropositivity, compared with individuals with awareness of their HCV status. In the HCV-seronegative group, compared with the participants who were aware of their HCV status, those with UoHCV were more likely to have a history of sexually transmitted diseases within the preceding 6 months and believe that intravenous injection was a requirement for contracting HCV. Moreover, they were less likely to have received higher education, previously heard of HCV infection, and received information on HCV infection from clinicians (Table 2).

Table 2

Bivariate and multivariable analyses of factors associated with UoHCV among PLWH stratified into two groups: HCV-seronegative group (n = 734) and HCV-seropositive group (n = 110).

			All participants			HCV-seronegative group		HCV-seropositive group
			% of UoHCV	Bivariate analysis, crude OR (95% CI)	Multivariable analysis, adjusted OR (95% CI)	% of UoHCV	Multivariable analysis, adjusted OR (95% CI)	% of UoHCV	Multivariable analysis, adjusted OR (95% CI)
Sociodemographic variables
• Period of HIV diagnosis
	Period 1 (before 2008)		46.9	Reference		60.5		15.1	Reference
	Period 2 (2008–2013)		54.5	1.357 (0.924–1.994)		58.7		16.0
	Period 3 (2014–2020)		60.2	1.713 (1.201–2.443)**		62.6		31.3	0.029 (0.001–0.918)*
• Gender
	Female		37.5	Reference		50.0		16.7
	Male		56.0	2.125 (0.765–5.900)		61.2		20.2
• Age, per 1-year increase			N/A	0.974 (0.961–0.988)***		N/A		N/A
• Education above college level
	No		60.5	Reference	Reference	70.5	Reference	19.5
	Yes		51.5	0.696 (0.529–0.915)**	0.481 (0.334–0.692)***	53.9	0.462 (0.317–0.673)***	21.2
• Employment
	No		61.7	Reference		71.0		23.3
	Yes		54.3	0.739 (0.517–1.057)		59.0		18.8
• Marriage
	No		57.2	Reference		61.3		22.2
	Yes		39.4	0.269 (0.135–0.535)***		57.1		13.8
• HIV diagnosis in Kaoping area
	No		61.0	Reference		63.2		33.3
	Yes		55.1	0.786 (0.493–1.253)		60.8		19.2
• HIV-related risk assessment
	MSM		57.1	Reference		60.3		25.9	Reference
	Heterosexual		62.9	0.204 (0.107–0.391)***		67.7		25.0
	Bisexual		60.9	0.254 (0.145–0.447)***		60.7		66.7
	PWID		11.4	0.625 (0.393–0.997)*		66.7		7.3	0.028 (0.001–0.877)*
• History of sexually-transmitted diseases within the preceding 6 months
	No		53.5	Reference	Reference	59.0	Reference	18.1
	Yes		66.0	1.690 (1.168–2.445)**	2.012 (1.261–3.212)**	70.1	2.190 (1.349–3.554)**	31.3
• Has your doctor ever provide you the information about your HCV infection status before
	No		76.8	Reference	Reference	79.1	Reference	41.4
	Yes		28.5	0.120 (0.088–0.164)***	0.167 (0.118–0.236)***	33.0	0.154 (0.107–0.222)***	12.3
• Have ever heard of HCV
	No		92.2	Reference	Reference	92.0	Reference	100.0
	Yes		46.8	0.075 (0.042–0.134)***	0.151 (0.081–0.283)***	52.3	0.158 (0.085–0.297)***	17.0
Laboratory data at time of questionnaire, n (%)
• HAV Ab seropositivity
	No		60.3	Reference		63.6		33.3	Reference
	Yes		3.3	0.754 (0.566–1.004)		59.6		14.7	0.015 (0.001–0.270)**
• HBs Ag seropositivity
	No		55.8	Reference		60.9		20.8
	Yes		56.0	1.006 (0.636–1.584)		63.4		15.4
• HCV Ab seropositivity
	No		61.0	Reference	Reference	N/A		N/A
	Yes		20.0	0.160 (0.098–0.261)***	0.428 (0.229–0.800)**	N/A		N/A
Perceived risk of HCV infection
• Only those who inject medication intravenously can get hepatitis C			N/A	1.527 (1.317–1.771)***	1.405 (1.162–1.699)***	N/A	1.402 (1.147–1.714)**	N/A	4.912 (1.130–21.358)*
• The sexual behavior styles that I like put me at risk of hepatitis C infection			N/A	1.099 (0.970–1.245)		N/A		N/A
• I am more worried about hepatitis C than HIV			N/A	0.964 (0.845–1.098)		N/A		N/A
Assessment of potential exposures to HCV
• Use of intravenous form of recreational drugs
	No use		56.9	Reference		60.1		25.7
	Yes, less than a year		68.6	1.654 (0.799–3.426)		82.1		14.3
	Yes, 1–3 years		55.0	0.927 (0.380–2.262)		66.7		20.0
	Yes, more than 3 years		15.2	0.135 (0.052–0.354)		60.0		7.1
• Engagement in chemosexual behaviors within the preceding 6 months
	No		54.4	Reference		60.3		17.0
	Yes		64.2	1.502 (0.990–2.282)		65.7		50.0
• Status of having a sexual partner within the preceding 6 months
	No sexual partner		55.7	Reference		64.3		19.7
	Regular sexual partner		53.9	0.930 (0.683–1.267)		58.1		19.4
	No regular sexual partners, less than 5 partners		56.9	1.052 (0.707–1.566)		59.4		27.3
	No regular sexual partner, more than 5 partners		64.0	1.414 (0.762–2.625)		66.7		0.0
• Sexual experiences within the preceding 6 months
	Ever experience sadomasochism
		No	55.9	Reference		61.3		19.8
		Yes	47.8	0.723 (0.315–1.657)		52.6		25.0
	Ever experience group sex participation
		No	55.0	Reference		60.6		20.0
		Yes	62.2	1.347 (0.843–2.152)		64.9		20.0
	Ever experience Insertive/receptive unprotected anal intercourse
		No	55.7	Reference		65.0		16.7
		Yes	55.7	1.000 (0.762–1.312)		57.8		28.1
	Ever experience vaginal sex
		No	56.3	Reference		61.5		20.6
		Yes	50.6	0.795 (0.510–1.240)		56.8		15.4

Note: *p < 0.05;

**p < 0.01;

***p < 0.001.

Abbreviations: Ab, antibody; Ag, antigen; HBs, hepatitis B surface; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PWID, people who inject drugs; MSM, men who have sex with men; N/A, not available; PLWH, people living with human immunodeficiency virus; UoHCV, unawareness of HCV infection status.

Development of the HCV knowledge scale among PLWH

The item analysis initially indicated that the original 15 items for measuring HCV knowledge exhibited satisfactory discriminant validity. Exploratory factor analysis finally identified three domains of the 15 items: route of HCV transmission (domain 1), HCV course and complications (domain 2), and HCV treatment (domain 3). Cronbach’s α revealed suitable reliability in the three domains, which were thus further analyzed (S1 Table).

Association between UoHCV and HCV-related knowledge scores stratified by HCV serostatus

Table 3 presents the correct response rates to the 15 HCV-related knowledge items among PLWH with and without awareness of their HCV status, stratified by HCV serostatus. Overall, the correct response rates to the questions ranged from 16.8% to 71.1%. The following three questions had the lowest rates of correct responses: “can hepatitis C virus infection be prevented by vaccines?” (16.8%), “does hepatitis C infection commonly not result in any symptoms?” (31.3%), and “does the successful treatment of hepatitis C virus infection prevent reinfection?” (39.3%). The question “can hepatitis C virus infection be treated?” had the highest proportion of correct responses (71.1%).

Table 3

Comparison of correct responses to structural questions on HCV knowledge between participants with and without awareness of their HCV status, stratified by HCV serostatus.

		Correct answer	HCV-seronegative group		P-value	HCV-seropositive group		P-value
			Unawareness	Awareness		Unawareness	Awareness
			N = 448	N = 286		N = 22	N = 88
Route of HCV transmission
	Does hepatitis C virus can be transmitted through the blood?	Yes	49.6%	82.2%	<0.001	68.2%	85.2%	0.064
	Does hepatitis C virus can be transmitted through sexual behaviors?	Yes	41.7%	73.8%	<0.001	59.1%	75.0%	0.138
	Does hepatitis C virus can be transmitted through mother-to-child vertical transmission?	Yes	41.1%	69.6%	<0.001	45.5%	69.3%	0.036
	Are the infection routes of HIV similar to those of the hepatitis C virus?	Yes	41.7%	72.7%	<0.001	59.1%	72.7%	0.212
	During sexual behaviors, does mucosa hemorrhage of sexual contact parts due to excessive intensity makes hepatitis C virus infection easier?	Yes	40.3%	76.2%	<0.001	57.9%	68.4%	0.386
	Is blood the major transmission routes of hepatitis C virus?	Yes	38.8%	61.5%	<0.001	54.5%	71.6%	0.125
Course and complication of HCV
	If you are infected with HIV, does this mean you are more likely to be infected with hepatitis C virus?	Yes	38.6%	67.5%	<0.001	72.7%	64.8%	0.480
	Does the successful treatment of hepatitis C virus infection prevent reinfection?	No	31.5%	47.2%	<0.001	40.9%	53.4%	0.294
	Hepatitis C virus mostly cures itself, and no treatment is needed	No	51.6%	75.2%	<0.001	63.6%	87.5%	0.008
	Does Hepatitis C infection commonly not result in any symptoms?	Yes	21.4%	42.3%	<0.001	27.3%	46.6%	0.101
	Do complications after hepatitis C virus infection include cirrhosis and liver cancer?	Yes	45.5%	78.0%	<0.001	59.1%	84.1%	0.01
	Does HIV increase complication probability after hepatitis C virus infection (such as cirrhosis and liver cancer)?	Yes	40.6%	66.8%	<0.001	45.5%	69.3%	0.036
Treatment of HCV
	Can hepatitis C virus infection be prevented by vaccines?	No	9.2%	21.7%	<0.001	31.8%	36.4%	0.690
	Can hepatitis C virus infection be treated?	Yes	57.8%	83.9%	<0.001	68.2%	97.7%	<0.001
	Can Hepatitis C virus infection be cured?	Yes	33.9%	53.5%	<0.001	40.9%	83.0%	<0.001

Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus.

Multilinear regression analyses revealed that UoHCV was associated with lower mean scores overall and for each domain of HCV-related knowledge compared with HCV status awareness, both in the HCV-seronegative group and the HCV-seropositive group (Table 4).

Table 4

Association of UoHCV with HCV knowledge scores, stratified by knowledge domain in a multivariable linear regression.

	Total score	Domain 1 (Route of HCV transmission)	Domain 2 (HCV course and complications)	Domain 3 (HCV treatment)
	Adjusted Model Estimate (β)(95% CI)	Adjusted Model Estimate (β)(95% CI)	Adjusted Model Estimate (β)(95% CI)	Adjusted Model Estimate (β)(95% CI)
Total participants
• Unawareness of HCV infection status	-0.232 (-0.271–-0.192)***	-0.271 (-0.321–-0.220)***	-0.217 (-0.262–-0.173)***	-0.190 (-0.232–-0.147)***
HCV-seronegative group
• Unawareness of HCV infection status	-0.239 (-0.281–-0.197)***	-0.283 (-0.337–-0.228)***	-0.222 (-0.270–-0.175)***	-0.182 (-0.227–-0.137)***
HCV-seropositive group
• Unawareness of HCV infection status	-0.195 (-0.305–-0.084)**	-0.189 (-0.337–-0.040)*	-0.177 (-0.301–-0.054)**	-0.282 (-0.404–-0.160)***

Note: *p < 0.05;

**p < 0.01;

***p < 0.001.

†Adjustments were made in the multilinear regression for the period since participants received their HIV diagnosis and for their gender, age, education level, employment status, marital status, site of HIV diagnosis, HIV risk factors, history of sexually transmitted diseases in the preceding 6 months, and history of HCV therapy.

Abbreviations: Ab, antibody; CI, confidence interval; HCV, hepatitis C virus.

Discussion

To the best of our knowledge, ours is the first study to reveal differences in the prevalence rates of UoHCV among PLWH; these rates were 61.0% in the HCV-seronegative group and 20.0% in the HCV-seropositive group. The prevalence rate in the HCV-seropositive group increased to 33.8% after the exclusion of participants with a history of HCV treatment, all of whom knew their HCV status. After stratification by HCV serostatus, the two groups differed in terms of their sociodemographic characteristics and laboratory variables associated with UoHCV, indicating the need for strategies to be tailored according to HCV serostatus when attempting to reduce UoHCV among PLWH.

Our results revealed a higher prevalence of UoHCV among MSM than among PWID (25.9% vs.7.3%, p = 0.037) in the HCV seropositive population. Since the 1990s, several measures have been implemented to promote HCV testing and to enhance the awareness of HCV infection status among PWID. These measures have achieved significant effects in increasing HCV status awareness [18, 38, 39]. The risk of sexual transmission of HCV was low in the 1990s [40]. However, since the mid-2000s, sexually transmitted HCV has been increasingly detected among sexually active MSM [6, 20]. The high prevalence of UoHCV among MSM may be attributable to their unawareness of their HCV seropositivity status due to the fundamental misunderstanding that HCV can only be contracted from intravenous exposure to infected blood (e.g., through the use of unsterile injection equipment and contaminated blood products). This explanation is supported by the finding that individuals in this study who believed that intravenous injection was a requirement for contracting HCV were more likely to have UoHCV. Furthermore, an increasing trend of MSM was observed in the HCV-seropositive PLWH group (28.3%, 68.0%, and 81.3% in periods 1, 2, and 3, respectively [p for trend < 0.001]; S2 Table), which is consistent with findings of another study conducted in Taiwan [41]. Therefore, substantial efforts are urgently required to implement interventions that reduce the prevalence rate of UoHCV among HIV-positive individuals with sexually transmitted HCV.

The lower prevalence of UoHCV among HCV-seropositive PLWH diagnosed in 2014–2020 compared with the prevalence among those diagnosed before 2008 may be attributable to the results of recent efforts to fight the spread of HCV. These efforts include the increase in publicity on HCV worldwide, newly available DAAs, and implementation of measures to ensure the affordability of oral DAA agents in Taiwan; such measures include national programs for using DAA agents to treat patients with advanced HCV (implemented in 2017–2018) and for providing treatment support to all eligible patients enrolled in Taiwan’s National Health Insurance program (2019–present) [42, 43]. This means that compared with before 2008, there is now a higher likelihood of primary physicians testing for HCV and identifying HCV seropositivity in people recently diagnosed as having HIV and informing them of their condition. Moreover, primary physicians may be more likely to inform individuals of their HCV-seropositive status when diagnosing them as having a coinfection with sexually transmitted HAV because of the emerging trend of concomitant sexually transmitted HAV and HCV among PLWH in Taiwan [41, 44].

Reducing the engagement in high-risk behavior is critical for reducing rates of HCV infection. People who have received treatment for HCV who have ongoing exposure to HCV are at risk of reinfection. Limiting such exposure is necessary for making continual progress toward eradication of the disease [45]. Studies have revealed that awareness of HCV infection status reduces engagement in high-risk behaviors among HCV-seropositive PWID [9-12]. However, a significant association was not observed between UoHCV and high-risk behaviors related to HCV infection in the present study, in which the majority (94.8%) of participants had sexually transmitted HIV infection. This finding has two possible explanations. First, individuals who were aware of their HCV status may not have known its transmission route (e.g., sexual transmission). Second, individuals may have known the transmission route but been unwilling or unable to alter their behavior accordingly. Our findings support the second explanation because the participants with awareness of their HCV-seropositive status had higher scores in knowledge domain 1 (route of HCV transmission) than those without awareness of their HCV-seropositive status, indicating that they did not alter their behavior despite knowing the HCV transmission route. The results of a cross-sectional online survey of 48 Australian MSM further support our findings. The survey revealed that most participants knew that HCV infection can be sexually transmitted between men. However, participants generally did not know how to prevent the sexual transmission of HCV [46]. Although notifying PWID of their HCV status can effectively reduce their engagement in high-risk behaviors [9-12], effective behavior modification approaches for reducing the sexual transmission of HCV in at-risk populations have yet to be identified. Moreover, interventions to reduce modifiable behavioral risk factors, such as condom distribution, the promotion of abstinence from illicit drugs, and advocacy for safe sex, may attract serious criticism because of the stigma associated with sex and drug use [47]. Therefore, to optimize the awareness of the HCV care cascade among HCV-seropositive PLWH [8], further research is necessary to identify effective interventions for modifiable behavioral risk factors and settings during the process of notifying patients of their HCV status to promote long-term reductions in behaviors that involve a high-risk of exposure to HCV [48].

In the HCV-seronegative population, the prevalence of UoHCV (61.0%) among PLWH reported in the present study is substantially higher than the prevalence of general population reported by a nationwide screening program in Taiwan (33.0%) [16], possibly because of the high proportion of MSM (76.6%) who believe that intravenous injection is a requirement for contracting HCV.

In the present study, only 288 (39.2%) of the 734 HCV-seronegative PLWH responded “yes” to the question “has your doctor ever provided information regarding HCV infection?” This number was unexpectedly low considering that these PLWH were undergoing follow-up every 1–3 months at HIV referral hospitals in Taiwan. According to Taiwan’s guidelines for HIV and acquired immunodeficiency syndrome, HCV-seronegative PLWH should undergo annual screening for HCV antibodies [49]. HIV experts may overlook the importance of informing PLWH of their HCV-seronegative status. However, our data revealed that UoHCV is associated with lower mean scores for total and domain-specific HCV-related knowledge compared with HCV status awareness among PLWH with HCV-seronegative status. Furthermore, young, sexually active PLWH may primarily consult and receive serostatus notifications of HCV infection from HIV experts because of the stigma and discrimination that PLWH may experience when consulting with non-HIV experts [50]. Therefore, HIV experts should notify sexually active PLWH of their HCV-seronegative status. This is especially crucial for individuals who believe that HCV can only be transmitted between PWID or who have been diagnosed as having a sexually transmitted disease within the preceding 6 months.

Overall, our study revealed that the correct response rate for questions on HCV-related knowledge varied considerably (16.8% to 71.1%). This finding provides a basis for targeting gaps in patient HCV knowledge during counseling. In our study, UoHCV was determined to be negatively associated with different aspects of HCV-related knowledge, which is considered critical for initiating treatment for HCV infection [28, 51]. The findings of the present study also indicate that interventions tailored to each patient’s HCV serostatus should be actively enforced to reduce the prevalence of UoHCV.

The present study has several strengths. This is the first study to analyze UoHCV among PLWH and identify different determinants associated with UoHCV among PLWH according to their HCV serostatus. The study results also aid in the customization of strategies according to their HCV serostatus for reducing the prevalence of UoHCV among PLWH. Second, no standardized, validated HCV knowledge scoring system for PLWH is currently available. This study provides clinically relevant, structural, and valid measurements of HCV-related knowledge among PLWH. This structural measure of HCV-related knowledge can be applied to assess HCV-related knowledge before and after HCV-related educational interventions. These findings can also be used to longitudinally assess the influence of knowledge regarding HCV transmission on patients’ engagement in high-risk behaviors associated with HCV infection after they have completed treatment interventions. However, this study also has several limitations. First, 525 patients were unwilling to participate, which might have caused selection bias. However, the demographic characteristics, HCV serostatus, and HIV-related risks did not differ between the enrolled and unwilling patients. Second, although the trained investigators instructed participants to recall their experiences to answer certain questions, inaccurate recall was unavoidable. Third, although the current study revealed no association between high-risk behaviors for HCV infection and UoHCV among HCV-seropositive and HCV-seronegative PLWH, this study had a cross-sectional design. Therefore, additional prospective cohort studies are warranted to further clarify changes in individuals’ engagement in high-risk behaviors after they have been notified of their HCV status. Finally, the participants in the present study were PLWH, most of whom were MSMs. Therefore, the findings may not be generalizable to all PLWH populations.

Conclusion

With the current availability of all-oral, interferon-free DAAs, which achieve a curative outcome in more than 90% of patients with HCV and require only 12 weeks of treatment, the eradication of HCV in prevalent areas is now possible [52]; however, our study revealed that the majority of PLWH in Taiwan were unaware of their HCV serostatus. In the present study, UoHCV was associated with lower scores in different domains of HCV-related knowledge, which is considered critical for initiating treatment for HCV infection and reducing the engagement in risky behaviors among affected individuals. This finding suggests that interventions should be implemented to reduce the prevalence of UoHCV, regardless of patients’ HCV serostatus. Because the factors associated with UoHCV differed between HCV-seronegative and HCV-seropositive PLWH, strategies for reducing UoHCV may be more effective if they target PLWH according to their HCV serostastus.

Questionnaire on HCV infection status and related knowledge among patients living with HIV.

(DOCX)

Click here for additional data file.

Validation of the original 15 questions on HCV knowledge.

(DOCX)

Click here for additional data file.

Trends of various HIV at-risk populations among HCV-seropositive patients living with HIV across three periods of HIV diagnosis.

(DOCX)

Click here for additional data file.

18 Mar 2021

PONE-D-20-37478

High prevalence of unawareness of HCV infection status among both anti-HCV seronegative and seropositive people living with human immunodeficiency virus in Taiwan

PLOS ONE

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Thank your for submitting your manuscript. It addressed an very important issue - the first step in the HCV cascade of care. Please note that the I as Academic Editor conducted the second review.

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Reviewer #1: Hepatitis C elimination is a global public health task. This research has addressed one important issue in this challenging program. Some comments/recommendations for the authors:

1. When describe the time period, “<2008” might be better changed into “before 2008”.

1.1 In the manuscript, “The participants were categorized into three distinct periods based on the date of 127 HIV diagnosis: before 2008 (period 1), 2008–2013 (period 2), and 2014–2020 (period 3).” – it meant the first confirmed diagnosis of HIV? The earliest date of diagnosis in the study hospitals? Patients do not overlap in the 3 periods. Please clearly describe if possible.

1.2 It seems the authors separate the 3 groups of HIV patients to imply different cohorts might have different (unawareness) of HCV. However, the title of Figure 2 may have misleading wordings. Recommend using more precise wordings.

2 Page 13, Column 3, Line 5 – “360 ()80.4” should be corrected.

3 Page 13, Column 3, Line 6 – “21 (4,7)” should be corrected.

4 Page 15, First line – “Unawareness of HCV infection status…” is not applicable (necessary) for analysis.

5 Page 39, First line – the answer for that is “Yes” not “Blood”.

Reviewer #2: Editor's Comments

This is an interesting paper that has some strengths, including the overall study question, the target population and the setting. Taiwan has a significant burden of HCV. With current DAA treatments which offer cure over 90% of those treated, awareness of infection is the first step to getting people engaged in that beneficial care. There are numerous weaknesses and editorial issues that the authors need to address before this is suitable for publication. There do remain many areas for English grammar and syntax improvement as well. Below I list these, including both major and minor issues, by paper section.

ABSTRACT

1. Line 11-12. Please clarify if unawareness was that the participant incorrectly identified being anti-HCV negative if they were truly anti-HCV positive and if they identified as anti-HCV positive but were truly anti-HCV negative. This will need to be made clear later in the manuscript as well.

2. Line 17: I think it would be more appropriate to use the term Men who have sex with men (MSM) rather than homosexual. This should also be changed throughout other parts of the manuscript as well.

3. Line 17: Pleas change the term 'injection drug users" to "people who inject drugs" (PWID) here and throughout the manuscript.

4. Line 10: less hearing of HCV before. I think what is meant is that few had previously heard of HCV infection prior to the research. If this is correct, please change it. (This is an English issue)

INTRODUCTION

1. Lines29-30: The term "Elimination" should probably be replaced. HCV Elimination is used as a term in public health referring to population level control.No one has achieved elimination from a public health perspective. I think that authors mean to say that treatment with DAAs results in cure in 90% or more of patients (i.e. it is true that virus is eliminated in the patients body). I suggest reframing this about cure (more patient centered).

If the authors want - they can note that treatment with DAAs 'can lead to elimination of HCV viremia and cure.

2. Line 33: this statement should include a reference/citation regarding reinfections among people who use drugs, (were highest incidence is)

3. line 35: change "among' to "to"

4. Line 43: regarding "41% in Germany" - this reference is very dated and this may have changed since 2014 when DAAs became available. Please update.

5. Line 46: Please change intravenous drug users (IDUs) to People who inject drugs (PWID) here and throughout the manuscript.

6. Line 45-46 - regarding change in behavior with awareness of HCV status - not all research shows that this happens. Consider these: https://pubmed.ncbi.nlm.nih.gov/25814695/ https://www.sciencedirect.com/science/article/abs/pii/S0376871609002294?via%3Dihub

7. Line 51: The only references cited for this statement are with respect to sexual transmission. Please add references regarding parenteral transmission, which is FAR more common than sexual transmission.

8. Line 52: This reference is with respect to India, what what you cite is true. However HIV is highly stigmatized there. Strengthen this statement with some data from a different area/region.

9. Line 53: add: "especially marginalized groups, which may contribute to a significantly decreased..."

10. Lines 54-55 - i think caution should be used when prioritizing one population over another. This has the effect of putting value on one population over another. It may be enough to state that this is a high priority population and cite guidelines for treatment of HCV in PLWH from Infectious Disease Society, and or other clinical groups.

You can consider deleting the word 'more' and 'than in the general population' in this line.

11. Line 58-59 I think this sentence is too strong and a little off the mark: awareness of serostatus would facilitate the next step in continuum of care - linking to a provider and potentially treatment, which are all necessary steps to elimination.

12. Line 70. Please describe the Domains.

MATERIALS AND METHODS

1. Line 80: in the last sentence that says Southern Taiwan has a high prevalence of HCV infection, please add: 'relative to -----where and how much--. This will give the reader more perspective.

2. Linnes 84-85: please clarify what the difference is between "perceived risk of HCV infection, and assessment of the risk of HCV infections". (after reading the survey and the results the latter is about 'potential exposures to HCV". I do recommend using this language about exposures vs. risk elsewhere in the manuscript.

3. Lines 96-97 - Again, I think the authors should consider changing the language for the last group to "assessment of potential exposures to HCV".

4. Lines 127-128: please state why these time periods were selected.

5. Lines 120-131: This English is a little awkward. Consider changing to: 'correctly identifying as anti-HCV positive', and UoHCV as 'incorrectly identifying as anti-HCV negative"

6. Line 131: change high risk behaviors to high risk exposures (it is less judgmental).

7. Line 134: what does 'status' refer to? the HCV status of sexual partners? Please clarify.

8. Line 142: again, what are the Domains - please describe these.

9. Line 152: Please omit the word univariate and use the word bivariate when describing analyses comparing two variables. (univariate describes one variable).

10: Line 153Clarify what statistic was used to assess bivariate associations (it is not clear why use binary backwards logistic regression?? ). this sentence should probably read: Binary logistic Binary regression was used to assess associations and calculate odds ratios in bivariate analyses between surveyed factors and UoHCV... in .

11. Line 163: Consider editing this to: To determine HCV-related knowledge and domain scores of knowledge independently associated with UoHCV, we used a multilinear regressions model with backward strategy. Also, please clarify why Backward approach was used.

RESULTS

1. Lines 176-177: State what the subgroups are in the text.

2. Table 2: please change the word 'univariable' to Bivariate in the title and in the Table.

3. Lines 245-247 - the domains noted here should be moved to methods. It is find to reiterate them here as well.

4. Table 4. Please Name the Domains, not just the number. in the table heading. Can you convert the Betas and 95% CI to adjusted odds ratios.

DISCUSSION

1. Line 276: Be very sure of this... it may be the first in a study of HIV positive people (but its not the first study to assess discordance in HCV status and knowledge of status.)

2. Lines 282-283: what does this mean (need for customized strategies). This sentence is too broad - customized to who? or should messages be broadened to other groups. Be more specific .

3. Line 285 and elsewhere: change IDU to PWID.

4. Line 290: delete 'prevalent among" and change to "increasingly detected"

5. Line 291 and elsewhere: change homosexuals to MSM.

6. Line 294: delete medical, and replace with injection

7. Line 295: delete "or sharing of unsterile equipment" as it is redundant with the above.

8. Line 302: add "HIV positive" before the word 'individuals'

9. Line 306: Add "newly available DAAs" to this sentence.

10. Lines 316-318: Reframe this sentence. There is risk of reinfection among people treated with HCV who have ongoing exposures. Limiting these is needed to maintain elimination progress.

11. Line 320 - others researchers have not seen behavior change: (i) https://www.sciencedirect.com/science/article/abs/pii/S0376871609002294?via%3Dihub

(ii) https://jech.bmj.com/content/69/8/745

But note that these studies were not conducted in PLWH

12. Line 336: When you say 'further research' be more engaged. Like what research is needed.

13. Lines 337-339: This is a very old reference. Many attitudes have changed. Does stigma remain high in Taiwan? Perhaps local reference might be better here to better frame what is needed in Taiwan.

14. Lines 341-342: delete part of the sentence that says: ..."particularly among individuals... before 2008"

15. Line 343: When saying additional study, should be conducted - like what ? besides condom use?

16. Line 354-355". What is the medical guideline for HCV testing in HIV positive people in Taiwan? this would be good information to share and make the point that the HCV testing rate is low in this high risk group.

17. Lines 357-358" The sentence states there is a negative association: please interpret this for our readers. What does this mean?

18. Several places -where Tables are referred to in the Discussion. I think you do not have to tell the reader to go back to the tables and can delete those.

19. Line 376: please make sure to state the population a the end of the sentence ".. in PLWH".

20: Line 388: Good job on the limitations. I suggest deleting the words "was unavoidable" from this sentence though.

21. Line 394 change this sentence to read: ".. findings may not be generalizable to all PLWH populations. [i feel that in many places the authors lose sight that this is all done in PLWH - so discussion points need to emphasize that].

CONCLUSION

1. Line 399" say why the 'era of DAA's is important (eg., the high cure rates and potential to impact population prevalence or lead to elimination...?)

2. Line 405: Delete the end of the sentence starting with 'should' and change to "may be more effective if targeted to PLWH by HCV serostastus. (stay with your data and your population'. (the word personalized is awkward)

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Reviewer #1: No

Reviewer #2: No

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11 Apr 2021

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Response:

We have revised it as PLOS ONE's style requirements.

2. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

Response:

We have added a new supplementary table 2 (S2_Table) in the revised manuscript.

Responses to the comments of the Reviewer 1

1. When describe the time period, “<2008” might be better changed into “before 2008”.

Answer:

Thank for the reviewer’s suggestion. We have corrected it throughout the manuscript.

2. In the manuscript, “The participants were categorized into three distinct periods based on the date of 127 HIV diagnosis: before 2008 (period 1), 2008–2013 (period 2), and 2014–2020 (period 3).” – it meant the first confirmed diagnosis of HIV? The earliest date of diagnosis in the study hospitals? Patients do not overlap in the 3 periods. Please clearly describe if possible.

Answer:

Thank for the reviewer’s suggestion, and we have revised it as “The participants were categorized by three distinct periods based on the calendar year of their first confirmed HIV diagnosis: before 2008 (period 1, before the remission of the HIV epidemic among PWID) [36], 2008–2013 (period 2, remission of the HIV epidemic among PWID but before the introduction of oral DAAs), and 2014–2020 (period 3, after the introduction of oral DAAs).” Materials and Methods section, line 139-143.

3. It seems the authors separate the 3 groups of HIV patients to imply different cohorts might have different (unawareness) of HCV. However, the title of Figure 2 may have misleading wordings. Recommend using more precise wordings.

Answer:

We have revised the title of figure 2 as “Fig 2. Trend analyses of prevalence of UoHCV stratified by HCV serostatus in three periods according to the calendar year of first confirmed HIV diagnosis ( period 1 [before 2008], period 2 [2008-2013], and period 3 [2014-2020]).” Result section, line 235-237.

4. Page 13, Column 3, Line 5 – “360 ()80.4” should be corrected.

Answer:

We have corrected it.

5. Page 13, Column 3, Line 6 – “21 (4,7)” should be corrected.

Answer:

We have corrected it.

6. Page 15, First line – “Unawareness of HCV infection status…” is not applicable (necessary) for analysis

Answer:

Thank for the reviewer’s suggestion, and we have deleted it.

7. Page 39, First line – the answer for that is “Yes” not “Blood”.

Answer:

Thank for the reviewer’s suggestion, and we have corrected it.

Responses to the comments of the Reviewer 2 (Academic editor)

ABSTRACT

1. Line 11-12. Please clarify if unawareness was that the participant incorrectly identified being anti-HCV negative if they were truly anti-HCV positive and if they identified as anti-HCV positive but were truly anti-HCV negative. This will need to be made clear later in the manuscript as well.

Answer:

Thank for the editor’s valuable suggestion. We will explain below:

In the manuscript under the Method section, we mentioned “awareness of HCV infection status was defined as participants’ self-reported recognition of their HCV infection status at the time of enrollment in the study (i.e., HCV-seropositive patients’ awareness of their HCV-positive status and HCV-seronegative patients’ awareness of their HCV-negative status), whereas UoHCV was defined as participants’ self-reported unawareness of their HCV infection status”. Materials and Methods section, line 144-149.

Therefore, for HCV seropositive group, awareness of HCV infection status mean that the individual recognize himself/herself as HCV-positive status (whether the awareness is correct or incorrect); for HCV seronegative group, awareness of HCV infection status mean that the individual recognize himself/herself as HCV-negative status.

However, the awareness of self-HCV infection status may be correct or incorrect. According to the study conducted by Cheryl et al. (J Glob Health . 2019 Jun;9(1):010426), the rate pf correctly aware of their HCV infection status was 44.6% for anti-HCV (+) and 66.3% for anti-HCV (-). However, the issue of the incorrect/correct awareness is not the goal of the present study. We appreciate the editor’s comments, and we may discuss it in the next study.

To clarify it in the abstract, we revised it as “HCV infection status awareness is crucial in the HCV care continuum for both HCV-seropositive (HCV-positive status awareness) and seronegative (HCV-negative status awareness) populations. However, trends in the unawareness of HCV infection status (UoHCV) remain unknown in HIV-positive patients. This study investigated UoHCV prevalence, the associated factors of UoHCV, and its association with HCV-related knowledge in HIV-positive patients.” Abstract section, line 2-7.

2. Line 17: I think it would be more appropriate to use the term Men who have sex with men (MSM) rather than homosexual. This should also be changed throughout other parts of the manuscript as well.

Answer:

Thank for the editor’s suggestion, and we have corrected it throughout the manuscript.

3. Line 17: Pleas change the term 'injection drug users" to "people who inject drugs" (PWID) here and throughout the manuscript.

Answer:

Thank for the editor’s suggestion, and we have corrected it throughout the manuscript.

4. Line 10: less hearing of HCV before. I think what is meant is that few had previously heard of HCV infection prior to the research. If this is correct, please change it. (This is an English issue).

Answer:

Thank for the editor’s suggestion, and we have corrected it as “participants with UoHCV were more likely to have a recent history of sexually transmitted diseases, but had a lower education level, had received less information on HCV infection from clinicians, and were less likely to have heard of HCV infection prior to the research”. Abstract section, line 21-24.

INTRODUCTION

1. Lines29-30: The term "Elimination" should probably be replaced. HCV Elimination is used as a term in public health referring to population level control. No one has achieved elimination from a public health perspective. I think that authors mean to say that treatment with DAAs results in cure in 90% or more of patients (i.e. it is true that virus is eliminated in the patients body). I suggest reframing this about cure (more patient centered).

If the authors want - they can note that treatment with DAAs 'can lead to elimination of HCV viremia and cure.

Answer:

Thank for the editor’s valuable suggestion. We have reframed it as “Although treatment with direct-acting antivirals (DAAs) can lead to the elimination of HCV viremia and a curative outcome in more than 90% of patients with chronic HCV infection,…..”. Introduction section, line 32-34.

2. Line 33: this statement should include a reference/citation regarding reinfections among people who use drugs, (were highest incidence is)

Answer:

Thank for the editor’s valuable suggestion. We have revised it as “several barriers to eradicating HCV infection still exist, including the high costs of drugs [3], frequent loss to follow-up after diagnosis [4], high rate of early HCV reinfection among patients who have recently received drug injections [5], and ongoing high-risk behaviors associated with HCV infection (even after clearance of HCV infection) [6].” Introduction section, line 34-38.

3. line 35: change "among' to "to"

Answer:

We have corrected it.

4. Line 43: regarding "41% in Germany" - this reference is very dated and this may have changed since 2014 when DAAs became available. Please update.

Answer:

Thank for the editor’s suggestion. However, we didn’t find out another updated reference about the prevalence of awarensss of self-HCV infection status in German in the era of DAAs. Therefore, we deleted this reference.

5. Line 46: Please change intravenous drug users (IDUs) to People who inject drugs (PWID) here and throughout the manuscript.

Answer:

Thank for the editor’s suggestion, and we have corrected it throughout the manuscript.

6. Line 45-46 - regarding change in behavior with awareness of HCV status - not all research shows that this happens. Consider these: https://pubmed.ncbi.nlm.nih.gov/25814695/ https://www.sciencedirect.com/science/article/abs/pii/S0376871609002294?via%3Dihub

Answer:

We thank for the editor’s valuable suggestions. The two studies aimed to evaluate the behavior change after notification of HCV infection status.

Brief introduction of the two studies were listed below:

1. https://www.sciencedirect.com/science/article/abs/pii/S0376871609002294?via%3Dihub:

This prospective study of 112 young PWID who experienced HCV seroconversion during follow-up demonstrated a modest reduction on alcohol and non-injection drug use that is not sustained over time after the young IDU were aware of their HCV seroconversion.

2. https://pubmed.ncbi.nlm.nih.gov/25814695/

This within-cohort matching study enrolled 190 HCV-positive and HCV-negative participnts at baseline. This study demonstrate a 5% per 3-month reduction post-notification in the odds of recent injection drug use (adjusted Odds Ratio: aOR 0.95, 95% CI 0.93–0.96) in HCV-positive group and a 8% per 3-month reduction post-notification in the odds of recent syringe borrowing (adjusted Odds Ratio: aOR 0.92, 95% CI 0.87–0.97) in HCV-negative group.

Therefore, we revised the paragraph as “Although the short- and long-term impacts of HCV-positive status awareness among HCV-seropositive patients on their risk behavior remain matters of debate [9-12], HCV-positive status awareness is essential in the HCV care continuum in terms of treatment eligibility and taking medical advice on viral transmission [12,13].” Introduction section, line 43-47. and as “In the HCV-seronegative population at risk of contracting HCV, people who inject drugs (PWID) may engage in high-risk behaviors (e.g., sharing a syringe or injecting themselves with drugs) less frequently if they are aware of their HCV infection status (i.e., HCV-negative status awareness) [9,12].” Introduction section, line 50-53.

7. Line 51: The only references cited for this statement are with respect to sexual transmission. Please add references regarding parenteral transmission, which is FAR more common than sexual transmission.

Answer:

Thank for the editor’s suggestion. We have added an another reference 21 (PLoS One. 2019 Dec 10;14(12):e0226166), as below:

“People living with human immunodeficiency virus (HIV) infection (PLWH) are at risk of HCV infection because the transmission routes of HCV infection, such as unprotected sex and drug injection, are similar to those of HIV infection [6,20,21].” Introduction section, line 56-58.

8. Line 52: This reference is with respect to India, what you cite is true. However HIV is highly stigmatized there. Strengthen this statement with some data from a different area/region.

Answer:

Thank for the editor’s suggestion, and we have added another two reference 23 (Drug Alcohol Depend. 2008 Jan 11;93(1-2):141-7) and 24 (J Acquir Immune Defic Syndr

. 2004 Nov 1;37(3):1367-75), and revised it as “Moreover, individuals coinfected with HCV and HIV are less likely to seek HCV care [22-24].” Introduction section, line 59-60.

9. Line 53: add: "especially marginalized groups, which may contribute to a significantly decreased..."

Answer:

Thank for the editor’s suggestion, and we have revised it as “Moreover, individuals coinfected with HCV and HIV are less likely to seek HCV care [22-24], which may contribute to a significantly decreased quality of life and quicker progression of liver disease, especially in those who are homeless or marginally housed [25].” Introduction section, line 59-62.

10. Lines 54-55 - I think caution should be used when prioritizing one population over another. This has the effect of putting value on one population over another. It may be enough to state that this is a high priority population and cite guidelines for treatment of HCV in PLWH from Infectious Disease Society, and or other clinical groups.

You can consider deleting the word 'more' and 'than in the general population' in this line.

Answer:

Thank for the editor’s valuable suggestion, and we have revised it as “Additionally, patients with HCV/HIV coinfection have higher rates of death and disease progression, including the progression of histological fibrosis/cirrhosis and decompensated liver disease, than do patients with HCV monoinfection [26]. Therefore, HCV screening, treatment, and prevention strategies should be strictly implemented among PLWH [27].” We also added a new reference 27: Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. 2021. Introduction section, line 62-66.

11. Line 58-59 I think this sentence is too strong and a little off the mark: awareness of serostatus would facilitate the next step in continuum of care - linking to a provider and potentially treatment, which are all necessary steps to elimination.

Answer:

Thank for the editor’s suggestion, and we have revised it as “Serostatus awareness facilitates the next step in the continuum of HCV care, namely providing affected patients with access to health care, relevant consultation, and potential treatment, which are necessary to eradicate HCV.” Introduction section, line 68-71.

12. Line 70. Please describe the Domains.

Answer:

We have revised it as “We evaluated the prevalence of UoHCV, explored the determinants of UoHCV, and evaluated the associations of UoHCV with different domains of HCV-related knowledge (i.e., route of HCV transmission, HCV course and complications, and HCV treatment) among a sample of PLWH stratified by HCV serostatus.” Introduction section, line 80-84.

MATERIALS AND METHODS

1. Line 80: in the last sentence that says Southern Taiwan has a high prevalence of HCV infection, please add: 'relative to -----where and how much--. This will give the reader more perspective.

Answer:

We have revised it as “The HCV seropositivity in southern Taiwan is 8.6% [31], which is higher than that in northern Taiwan (1.2%–2.7%) [32].” Materials and Methods section, line 92-93.

2. Lines 84-85: please clarify what the difference is between "perceived risk of HCV infection, and assessment of the risk of HCV infections". (after reading the survey and the results the latter is about 'potential exposures to HCV". I do recommend using this language about exposures vs. risk elsewhere in the manuscript.

Answer:

Thank for the editor’s suggestion, and we have revised it throughout the manuscript.

3. Lines 96-97 - Again, I think the authors should consider changing the language for the last group to "assessment of potential exposures to HCV".

Answer:

Thank for the editor’s suggestion. We have revised it throughout the manuscript and the S1 file.

4. Lines 127-128: please state why these time periods were selected.

Answer:

We have revised it as “The participants were categorized by three distinct periods based on the calendar year of their first confirmed HIV diagnosis: before 2008 (period 1, before the remission of the HIV epidemic among PWID) [36], 2008–2013 (period 2, remission of the HIV epidemic among PWID but before the introduction of oral DAAs), and 2014–2020 (period 3, after the introduction of oral DAAs).” Materials and Methods section, line 139-143.

5. Lines 120-131: This English is a little awkward. Consider changing to: 'correctly identifying as anti-HCV positive', and UoHCV as 'incorrectly identifying as anti-HCV negative"

Answer:

As we have mentioned earlier. In the manuscript under the Method section, we defined awareness of HCV infection status as “participants’ self-reported recognition of their HCV infection status at the time of enrollment in the study (i.e., HCV-seropositive patients’ awareness of their HCV-positive status and HCV-seronegative patients’ awareness of their HCV-negative status). Materials and Methods section, line 144-147.

Therefore, for HCV seropositive group, awareness of HCV infection status mean that the individual recognize himself/herself as HCV-positive status (whether the awareness is correct or incorrect); for HCV seronegative group, awareness of HCV infection status mean that the individual recognize himself/herself as HCV-negative status.

To clarify it, we have revised it as “In this study, awareness of HCV infection status was defined as participants’ self-reported recognition of their HCV infection status at the time of enrollment in the study (i.e., HCV-seropositive patients’ awareness of their HCV-positive status and HCV-seronegative patients’ awareness of their HCV-negative status), whereas UoHCV was defined as participants’ self-reported unawareness of their HCV infection status [8,16].” Materials and Methods section, line 144-149.

6. Line 131: change high risk behaviors to high risk exposures (it is less judgmental).

Answer:

Thank for the editor’s suggestion, and we have revised it as “The behavioral indicators of a high risk of exposure to HCV infection were modified from other studies and included using any intravenous recreational drugs [12], engaging in chemosexual behaviors within the preceding 6 months [37], having a sexual partner within the preceding 6 months (assessment options were no sexual partners, one regular sexual partner, no regular sexual partners/less than five partners, and no regular sexual partner/more than five partners) [37], and engaging in other activities involving sexual contact within the preceding 6 months [37].” Materials and Methods section, line 150-156.

7. Line 134: what does 'status' refer to? the HCV status of sexual partners? Please clarify.

Answer:

Thank for the editor’s suggestion, and we have revised it as “having a sexual partner within the preceding 6 months (assessment options were no sexual partners, one regular sexual partner, no regular sexual partners/less than five partners, and no regular sexual partner/more than five partners) [37], and engaging in other activities involving sexual contact within the preceding 6 months [37]” Materials and Methods section, line 152-155.

We also revised it in the table 1 and 2.

8. Line 142: again, what are the Domains - please describe these.

Answer:

We have revised it as “Secondary outcomes were factors associated with UoHCV and the associations of UoHCV with the mean scores for three domains of HCV knowledge (route of HCV transmission, HCV course and complications, and HCV treatment) among the participants stratified by their HCV serostatus.” Materials and Methods section, line 160-164.

9. Line 152: Please omit the word univariate and use the word bivariate when describing analyses comparing two variables. (univariate describes one variable).

Answer:

Thank for the editor’s valuable suggestion, and we have corrected it as the editor’s suggestion.

10: Line 153Clarify what statistic was used to assess bivariate associations (it is not clear why use binary backwards logistic regression?? ). this sentence should probably read: Binary logistic Binary regression was used to assess associations and calculate odds ratios in bivariate analyses between surveyed factors and UoHCV... in .

Answer:

Thank for the editor’s valuable suggestion, and we have revised it as “Backward stepwise binary logistic regressions were performed to calculate odds ratios and evaluate associations in the bivariate and multivariable analyses between surveyed factors and UoHCV among all the participants and among those in the two HCV serostatus groups. To simultaneously consider the effects of all variables in the multivariable model, we adopted a backward approach.” Materials and Methods section, line 174-178.

11. Line 163: Consider editing this to: To determine HCV-related knowledge and domain scores of knowledge independently associated with UoHCV, we used a multilinear regressions model with backward strategy. Also, please clarify why Backward approach was used.

Answer:

Thank for the editor’s valuable suggestion, and we have revised it as “Finally, to determine the association of UoHCV with the means of the total and domain-specific scores of HCV-related knowledge, we employed a multilinear regression model with a backward approach. β along with 95% confidence intervals were calculated to estimate the effects of UoHCV and directions of all associations. A backward approach was also adopted to enable the effects of all the variables to be simultaneously considered in the multivariable model.” Materials and Methods section, line 188-193.

RESULTS

1. Lines 176-177: State what the subgroups are in the text.

Answer:

Thank for the editor’s valuable suggestion, and we have revised it as “A total of 844 PLWH were included in the final analysis. They were divided into HCV-seronegative (n = 734) and HCV-seropositive (n = 110) groups. The two groups were further divided into subgroups 1 (unawareness/HCV-seronegative; n = 448), 2 (awareness/HCV-seronegative; n = 286), 3 (unawareness/HCV-seropositive; n = 22), and 4 (awareness/HCV-seropositive; n = 88).” Results section, line 202-207.

2. Table 2: please change the word 'univariable' to Bivariate in the title and in the Table.

Answer:

Thank for the editor’s valuable suggestion, and we have corrected it.

3. Lines 245-247 - the domains noted here should be moved to methods. It is find to reiterate them here as well.

Answer:

Thank for the editor’s valuable suggestion, and we have revised it in the Materials and Methods under the section of “statistical analysis”, as ” We also performed exploratory factor analysis by using principal axis factoring with varimax rotation to investigate the structural domain of the 15 items, and three domains were finally categorized: route of HCV transmission (domain 1), HCV course and complications (domain 2), and HCV treatment (domain 3).” Materials and Methods section, line 181-185.

4. Table 4. Please Name the Domains, not just the number. in the table heading. Can you convert the Betas and 95% CI to adjusted odds ratios.

Answer:

Thank for the editor’s valuable suggestion, and we have added the name of each domain in Table 4.

For the association of UoHCV with HCV knowledge scores, the outcome “HCV knowledge” in multivariable model is continuous variable. Therefore, we used multilinear regressions model for analysis, and used “β” (for continuous outcome) to estimate the effect (odds ratios is used for categorical outcome). We also revised it as “β along with 95% confidence intervals were calculated to estimate the effects of UoHCV and directions of all associations.” Materials and Methods section, line 190-191.

DISCUSSION

1. Line 276: Be very sure of this... it may be the first in a study of HIV positive people (but its not the first study to assess discordance in HCV status and knowledge of status.)

Answer:

Thank for the editor’s valuable suggestion, and we have revised it as “To the best of our knowledge, ours is the first study to reveal differences in the prevalence rates of UoHCV among PLWH; these rates were 61.0% in the HCV-seronegative group and 20.0% in the HCV-seropositive group. The prevalence rate in the HCV-seropositive group increased to 33.8% after the exclusion of participants with a history of HCV treatment, all of whom knew their HCV status. After stratification by HCV serostatus, the two groups differed in terms of their sociodemographic characteristics and laboratory variables associated with UoHCV, indicating the need for strategies to be tailored according to HCV serostatus when attempting to reduce UoHCV among PLWH.” Discussion section, line 309-317.

2. Lines 282-283: what does this mean (need for customized strategies). This sentence is too broad - customized to who? or should messages be broadened to other groups. Be more specific.

Answer:

Thank for the editor’s valuable suggestion, and we have revised it as “After stratification by HCV serostatus, the two groups differed in terms of their sociodemographic characteristics and laboratory variables associated with UoHCV, indicating the need for strategies to be tailored according to HCV serostatus when attempting to reduce UoHCV among PLWH.” Discussion section, line 313-317.

3. Line 285 and elsewhere: change IDU to PWID.

Answer:

Thank for the editor’s suggestion, and we have corrected it throughout the manuscript.

4. Line 290: delete 'prevalent among" and change to "increasingly detected"

Answer:

Thank for the editor’s suggestion. We have revised it as “However, since the mid-2000s, sexually transmitted HCV has been increasingly detected among sexually active MSM”. Discussion section, line 323-325.

5. Line 291 and elsewhere: change homosexuals to MSM.

Answer:

Thank for the editor’s suggestion, and we have corrected it throughout the manuscript.

6. Line 294: delete medical, and replace with injection

Answer:

Thank for the editor’s suggestion, and we have revised it as “(e.g., through the use of unsterile injection equipment and contaminated blood products)”. Discussion section, line 328-329.

7. Line 295: delete "or sharing of unsterile equipment" as it is redundant with the above.

Answer:

Thank for the editor’s suggestion, and we have deleted it.

8. Line 302: add "HIV positive" before the word 'individuals'

Answer:

Thank for the editor’s suggestion, and we have added it.

9. Line 306: Add "newly available DAAs" to this sentence.

Answer:

We have revised it as “These efforts include the increase in publicity on HCV worldwide, newly available DAAs, and implementation of measures to ensure the affordability of oral DAA agents in Taiwan.” Discussion section, line 340-342.

10. Lines 316-318: Reframe this sentence. There is risk of reinfection among people treated with HCV who have ongoing exposures. Limiting these is needed to maintain elimination progress.

Answer:

We have revised it as “Reducing the engagement in high-risk behavior is critical for reducing rates of HCV infection. People who have received treatment for HCV who have ongoing exposure to HCV are at risk of reinfection. Limiting such exposure is necessary for making continual progress toward eradication of the disease.” Discussion section, line 353-356.

11. Line 320 - others researchers have not seen behavior change: (i) https://www.sciencedirect.com/science/article/abs/pii/S0376871609002294?via%3Dihub

(ii) https://jech.bmj.com/content/69/8/745

But note that these studies were not conducted in PLWH

Answer

Brief introduction of the two studies:

1. https://www.sciencedirect.com/science/article/abs/pii/S0376871609002294?via%3Dihub:

This prospective study of 112 young PWID who experienced HCV seroconversion during follow-up demonstrated a modest reduction on alcohol and non-injection drug use that is not sustained over time after the young IDU were aware of their HCV seroconversion.

2. https://pubmed.ncbi.nlm.nih.gov/25814695/

This within-cohort matching study enrolled 190 HCV-positive and HCV-negative participnts at baseline. This study demonstrate a 5% per 3-month reduction post-notification in the odds of recent injection drug use (adjusted Odds Ratio: aOR 0.95, 95% CI 0.93–0.96) in HCV-Positive group and a 8% per 3-month reduction post-notification in the odds of Recent syringe borrowing (adjusted Odds Ratio: aOR 0.92, 95% CI 0.87–0.97) in HCV-Negative group.

These two studies provided evidence of reduction of HCV-risk behaviors post-notification of HCV status. We revised it as “Studies have revealed that awareness of HCV infection status reduces engagement in high-risk behaviors among HCV-seropositive PWID [9-12]. However, a significant association was not observed between UoHCV and high-risk behaviors related to HCV infection in the present study, in which the majority (94.8%) of participants had sexually transmitted HIV infection.” Discussion section, line 356-361.

12. Line 336: When you say 'further research' be more engaged. Like what research is needed.

Answer:

We have revised it as “Therefore, to optimize the awareness of the HCV care cascade among HCV-seropositive PLWH [8], further research is necessary to identify effective interventions for modifiable behavioral risk factors and settings during the process of notifying patients of their HCV status to promote long-term reductions in behaviors that involve a high-risk of exposure to HCV [48].” Discussion section, line 379-383.

13. Lines 337-339: This is a very old reference. Many attitudes have changed. Does stigma remain high in Taiwan? Perhaps local reference might be better here to better frame what is needed in Taiwan.

Answer:

Thank for the editor’s valuable suggestion. We have replaced the old reference with a new reference 47“AIDS Patient Care STDS. 2020 Jul;34(7):303-315”, and revised it as “Moreover, interventions to reduce modifiable behavioral risk factors, such as condom distribution, the promotion of abstinence from illicit drugs, and advocacy for safe sex, may attract serious criticism because of the stigma associated with sex and drug use [47].” Discussion section, line 375-379.

14. Lines 341-342: delete part of the sentence that says: ..."particularly among individuals... before 2008"

Answer:

We have deleted it as the editor’s suggestion.

15. Line 343: When saying additional study, should be conducted - like what ? besides condom use?

Answer:

We have rewritten the sentence to reduce the redundancy: Although notifying PWID of their HCV status can effectively reduce their engagement in high-risk behaviors [9-12], effective behavior modification approaches for reducing the sexual transmission of HCV in at-risk populations have yet to be identified. Moreover, interventions to reduce modifiable behavioral risk factors, such as condom distribution, the promotion of abstinence from illicit drugs, and advocacy for safe sex, may attract serious criticism because of the stigma associated with sex and drug use [47]. Therefore, to optimize the awareness of the HCV care cascade among HCV-seropositive PLWH [8], further research is necessary to identify effective interventions for modifiable behavioral risk factors and settings during the process of notifying patients of their HCV status to promote long-term reductions in behaviors that involve a high-risk of exposure to HCV [48]. Discussion section, line 372-383.

16. Line 354-355". What is the medical guideline for HCV testing in HIV positive people in Taiwan? this would be good information to share and make the point that the HCV testing rate is low in this high risk group.

Answer:

Thank for the editor’s valuable suggestion, and have added “According to Taiwan’s guidelines for HIV and acquired immunodeficiency syndrome, HCV-seronegative PLWH should undergo annual screening for HCV antibodies [49].” Discussion section, line 393-394.

17. Lines 357-358" The sentence states there is a negative association: please interpret this for our readers. What does this mean?

Answer:

Thank for the editor’s valuable suggestion, and we have revised it as “However, our data revealed that UoHCV is associated with lower mean scores for total and domain-specific HCV-related knowledge compared with HCV status awareness among PLWH with HCV-seronegative status.” Discussion section, line 396-398.

18. Several places -where Tables are referred to in the Discussion. I think you do not have to tell the reader to go back to the tables and can delete those.

Answer:

We have deleted it throughout the manuscript.

19. Line 376: please make sure to state the population a the end of the sentence ".. in PLWH".

Answer:

We have revised it as “This is the first study to analyze UoHCV among PLWH and identify different determinants associated with UoHCV among PLWH according to their HCV serostatus. The study results also aid in the customization of strategies according to their HCV serostatus for reducing the prevalence of UoHCV among PLWH.” Discussion section, line 414-418.

20: Line 388: Good job on the limitations. I suggest deleting the words "was unavoidable" from this sentence though.

Answer:

If the words “was unavoidable”, this would not be a whole sentence. Therefore, we decided to keep “was unavoidable”, but revised it as “Second, although the trained investigators instructed participants to recall their experiences to answer certain questions, inaccurate recall was unavoidable.” Discussion section, line 429-431.

21. Line 394 change this sentence to read: ".. findings may not be generalizable to all PLWH populations. [i feel that in many places the authors lose sight that this is all done in PLWH - so discussion points need to emphasize that].

Answer:

Thank for the editor’s valuable suggestion. We have revised it as “Finally, the participants in the present study were PLWH, most of whom were MSMs. Therefore, the findings may not be generalizable to all PLWH populations.” Discussion section, line 436-438.

CONCLUSION

1. Line 399" say why the 'era of DAA's is important (eg., the high cure rates and potential to impact population prevalence or lead to elimination...?)

Answer:

We have revised it as “With the current availability of all-oral, interferon-free DAAs, which achieve a curative outcome in more than 90% of patients with HCV and require only 12 weeks of treatment, the eradication of HCV in prevalent areas is now possible [52]; however, our study revealed that the majority of PLWH in Taiwan were unaware of their HCV serostatus.” Conclusion section, line 441-445.

2. Line 405: Delete the end of the sentence starting with 'should' and change to "may be more effective if targeted to PLWH by HCV serostastus. (stay with your data and your population'. (the word personalized is awkward)

Answer:

We have revised it as the editor’s suggestion. “Because the factors associated with UoHCV differed between HCV-seronegative and HCV-seropositive PLWH, strategies for reducing UoHCV may be more effective if they target PLWH according to their HCV serostastus.” Conclusion section, line 449-452.

Submitted filename: Response to Reviewers.docx

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21 Apr 2021

High prevalence of unawareness of HCV infection status among both HCV-seronegative and seropositive people living with human immunodeficiency virus in Taiwan

PONE-D-20-37478R1

Dear Dr. Lu,

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Additional Editor Comments (optional):

Thanks to the authors for their considerate and responsive revisions.

Reviewers' comments:

26 Apr 2021

PONE-D-20-37478R1

High prevalence of unawareness of HCV infection status among both HCV-seronegative and seropositive people living with human immunodeficiency virus in Taiwan

Dear Dr. Lu:

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