Incidence of HCV Reinfection Among HIV-Positive MSM and Its Association With Sexual Risk Behavior: A Longitudinal Analysis

Abstract

Background

Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at high risk of hepatitis C virus (HCV) reinfection following clearance of HCV, but risk factors specifically for reinfection have never been comprehensively assessed.

Methods

Using data from a prospective observational cohort study among HIV-positive MSM with an acute HCV infection (MOSAIC), the incidence of HCV reinfection following spontaneous clearance or successful treatment was assessed. A univariable Bayesian exponential survival model was used to identify risk factors associated with HCV reinfection.

Results

In total, 122 HIV-positive MSM who had a spontaneously cleared or successfully treated HCV infection between 2003 and 2017 were included. During a median follow-up of 1.4 years (interquartile range [IQR] 0.5–3.8), 34 HCV reinfections were observed in 28 patients. The incidence of HCV reinfection was 11.5/100 person-years and among those with reinfection, median time to reinfection was 1.3 years (IQR 0.6–2.7). HCV reinfection was associated with receptive condomless anal intercourse, sharing of sex toys, group sex, anal rinsing before sex, ≥10 casual sex partners in the last 6 months, nadir CD4 cell count <200 cells/mm³, and recent CD4 cell count <500 cells/mm³.

Conclusions

Incidence of HCV reinfection was high and strongly associated with sexual risk behavior, highlighting the need for interventions to reduce risk behavior and prevent HCV reinfections among HIV-positive MSM.

acute hepatitis C virus infection, MSM, risk factors, HCV reinfection incidence

Since 2000, increased rates of sexually transmitted hepatitis C virus (HCV) infection have been documented among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) [1–3]. Viral clearance of primary HCV infection, either spontaneous or treatment induced, does not confer sterilizing immunity against subsequent HCV reinfection [4, 5]. Most studies on HCV reinfection among HIV-positive MSM have found incidence rates between 5 and 10/100 person-years of follow-up [6–13], with estimates as low as 2.5/100 person-years [14, 15] and as high as 15/100 person-years [16, 17]. The incidence rate of second reinfection is even higher and can be up to 20/100 person-years [6, 7].

Little is known about behavioral factors associated with HCV reinfection. Some studies have reported that risk factors for initial HCV infection, such as injecting drug use, fisting, and condomless anal intercourse, were also present in MSM acquiring reinfection [8, 9, 16]. Furthermore, reinfection rates seem lower in those who spontaneously cleared their HCV infection [6, 7] and in those whose duration from primary HCV infection to treatment initiation was longer [12]. However, due to relatively small sample sizes, lack of control group including MSM without HCV reinfection, or lack of time-updated data on sexual risk behavior, factors associated with HCV reinfection among HIV-positive MSM have never been comprehensively assessed.

Identifying MSM at greatest risk of HCV reinfection is important for several reasons. First, targeted testing and counseling of these MSM could help curb the HCV epidemic. Second, as direct antiviral agents (DAAs) offer shorter treatment duration and minimal side effects compared with older treatment regimens, including pegylated-interferon (peg-IFN) and ribavirin, the perceived threat of HCV among HIV-positive MSM could be decreased, which might lead to an increase in risk-taking behavior and consequently an increase in HCV (re)infection rates [18, 19]. Third, HCV RNA testing is recommended for all MSM at risk of HCV reinfection [20, 21] but is costly and therefore needs prioritization to those with the highest risk of HCV reinfection. Hence, knowledge about the determinants for HCV reinfection is urgently needed.

Using data of the MSM Observational Study of Acute Infection with hepatitis C (MOSAIC), we assessed the incidence of HCV reinfection following HCV spontaneous clearance or successful treatment among HIV-positive MSM and examined clinical and behavioral risk factors associated with HCV reinfection.

METHODS

Study Population and Data Collection

Data from HIV-positive MSM enrolled in the MOSAIC were used. The MOSAIC is an observational cohort study initiated in 2009 in collaboration with the Public Health Service of Amsterdam and the Dutch HIV Monitoring Foundation and was conducted in 6 large HIV outpatient clinics in the Netherlands (4 in Amsterdam, 1 in Rotterdam, and 1 in Utrecht). Study procedures were described in detail elsewhere [22]. Briefly, HIV-positive MSM with an acute HCV infection were included, provided that they had had a confirmed acute HCV infection at any moment prior to inclusion, and followed over time. Sociodemographic, clinical, and virological data for both HIV and HCV were retrospectively collected from primary HCV infection and prospectively collected at each semi-annual visit following inclusion, together with an extensive self-administered questionnaire containing questions about drug use and sexual risk behavior. All participants gave written informed consent. The MOSAIC study was approved by the Institutional Review Boards of the Amsterdam UMC (University of Amsterdam, Amsterdam, the Netherlands) and boards of directors of all participating centers. For the present study, participants with at least 1 risk behavior questionnaire after spontaneous viral clearance or successful HCV treatment were included.

Definitions and Outcome

Acute HCV infection was defined as a positive anti-HCV antibody or HCV RNA test, preceded by at least 1 negative anti-HCV antibody and/or negative HCV RNA test result with a maximum interval of 365 days between the last negative and first positive test. The estimated date of infection was the midpoint between the last negative and first positive test result. For MSM without detectable HCV antibodies at the first HCV RNA positive test result, the estimated date of infection was determined as 28 days prior, which is equivalent to half of the mean seroconversion time [5]. Testing for anti-HCV antibody and HCV RNA were performed using commercially available assays, according to local laboratory procedures [22]. Spontaneous viral clearance was defined as 2 negative HCV RNA tests following a HCV positive RNA test in HCV untreated patients. The date of spontaneous clearance was estimated as the midpoint between the last positive and first negative HCV RNA test. Treatment consisted of peg-IFN with/without ribavirin or DAAs with/without ribavirin, depending on which regimen was recommended by guidelines at the time of treatment initiation. Sustained virological response (SVR) was defined as having at least 1 negative HCV RNA test 12 or 24 weeks after the end of treatment (depending on treatment regimen) or SVR as indicated in the patient’s medical file. Following HCV clearance (spontaneously or treatment induced), participants were tested for the presence of HCV RNA every 6 months at physician’s discretion, with any additional testing if HCV reinfection was suspected. Reinfection was defined as having a positive HCV RNA test after HCV clearance. If primary infection and reinfection were of the same HCV genotype and subtype, phylogenetic analysis was performed (preferably the E2/HVR1 region) to confirm infection with genetically divergent strains. In the absence of phylogenetic analysis, reinfections of the same HCV genotype and subtype were classified as possible reinfection. The date of reinfection was estimated as the midpoint between the last negative and first positive HCV RNA test. If a reinfection occurred during the period after end of treatment (12 or 24 weeks), treatment response was regarded as SVR.

Statistical Analyses

Follow-up began at the end of treatment or the date of spontaneous clearance and continued until estimated date of HCV reinfection for those who had a reinfection or last negative HCV RNA test for those who did not have a reinfection. Participants who cleared their reinfection (spontaneously or treatment-induced) became at risk again for subsequent reinfection. The incidence rate (IR) of reinfection and its corresponding 95% confidence interval (CI) were calculated using person-time methods. The cumulative incidence of first reinfection during follow-up was estimated by Kaplan-Meier methods.

In risk factor analyses, we took data from repeated questionnaires, and hence covariates changing over time were treated as time-updated. Clinical covariates were taken as the closest measurement to the date of a study visit. As questions referred to behavior during the last 6 months, MSM with only 1 questionnaire per year were assumed to have had the same behavior over the entire year. If data were missing, data were imputed from the subsequent visit with available data. Potential behavioral risk factors for HCV reinfection (eg, sharing of sex toys) were defined as present if they were performed with casual partners or with a steady partner whose HCV status was positive or unknown, and as absent if they were not performed at all or with an HCV negative steady partner [22]. For those with HCV reinfection, the questionnaire data from the visit closest to, but between 1 year before and 1 month after the date of diagnosis of HCV reinfection, was taken, as knowing HCV diagnosis might influence risk behavior. For these analyses, follow-up was additionally censored at the last study visit with available questionnaire data among those without reinfection. Those whose first study visit with questionnaire data was more than 12 months after HCV clearance entered the risk set (ie, left truncation) 6 months before the date of first study visit. Continuous variables were categorized as followed: age, <40/40–49/>50 years; nadir CD4 cell count, </>200 cells/mm³; CD4 cell count, </>500 cells/mm³; number of sex partners, 0/<10/>10; time between estimated date of HCV infection and start of HCV treatment, </>6 months.

Because few HCV reinfections were expected, we supposed that parameter estimates from standard regression techniques could be exaggerated and uncertain [23]. To minimize this bias, a penalized regression approach was used whereby uncertain estimates from the data are pulled toward more realistic ones assumed from prior knowledge [24]. Briefly, exponential survival models were fit for each covariate separately using a Bayesian approach. For each risk-factor, first a prior distribution of hazard ratios (HRs) was specified based on their anticipated strength of association [25] (Supplementary Table 1). These distributions were assigned after independent review by 3 researchers using previous studies assessing risk factors for initial acute HCV infection among HIV-positive MSM and for HCV reinfection among HIV-positive individuals (Supplementary Table 2). Disagreement between prior distributions was discussed until consensus was reached. Priors for covariates for which no previous studies were available were postulated (Supplementary Table 2). Because the intercept of this model estimates the IR without a given risk-factor, the prior distribution of this parameter was based on the HCV reinfection IR from a study of MSM in Canada with low risk behavior [15], estimated at 1.0 per 100 person-years (95% credible interval [CrI] .3–4.0). Using these priors together with the data, a posterior distribution of HRs was estimated with Markov Chain Monte Carlo methods from the “Bayes” prefix commands in Stata. The median of this distribution defined the parameter estimate (termed “posterior-HR”), and their 2.5% and 97.5% quantiles defined the 95% CrI. Analyses were performed using Stata version 15.1 (StataCorp LP, College Station, TX, USA).

Sensitivity Analyses

First, reinfection incidence was assessed excluding MSM with possible reinfections. Second, because specification of the prior distribution can influence posterior HRs [26], risk factor analysis was repeated using (1) noninformative priors for each covariate and (2) a different prior distribution for start of treatment >6 months from estimated date of HCV infection, rectal bleeding, and age >50. Furthermore, risk factor analysis was restricted to those at risk for first reinfection and to visits without missing data.

RESULTS

Study Population

In total, 122 HIV-positive MSM who resolved their HCV infection (spontaneously or treatment-induced) between 2003 and 2017 were included. Of those, 110 MSM began follow-up after their first HCV infection and 12 MSM after their second HCV infection (first reinfection). SVR following treatment with peg-IFN and ribavirin was achieved in 85, SVR following treatment with DAA in 27, and 10 had spontaneous viral clearance. Characteristics of the study population at baseline (end of treatment or estimated date of spontaneous clearance) and during follow-up are shown in Table 1.

Table 1.

Characteristics of HIV-positive MSM Participating in the MOSAIC Study at Risk of Hepatitis C Virus Reinfection, at Baseline and Follow-up

	All (N = 122), median (IQR) or number (%)	Not Reinfected at the End of Follow-up (N = 94), median (IQR) or number (%)	Reinfected During Follow-up (N = 28), median (IQR) or number (%)
BASELINE
Sociodemographic characteristics
Age, years	45.5 (39.5–49.7)	45.7 (40.0–49.7)	43.2 (38.1–50.0)
Dutch origin	102 (83.6%)	78 (83.0%)	24 (85.7%)
High educational levela	86 (71.7%)	66 (71.7%)	20 (71.4%)
HIV clinical characteristics
CD4 cell count (cells/mm3)	383 (295–574)	390 (300–580)	325 (245–535)
Nadir CD4 cell count (cells/mm3)a	270 (155–365)	280 (146–410)	225 (185–310)
On cART	107 (87.7%)	83 (88.3%)	24 (85.7%)
Undetectable HIV RNA (<50 copies/ mL)	103 (84.4%)	81 (86.2%)	22 (78.6%)
HCV clinical characteristics
Calendar year of HCV cure	2012 (2010–2014)	2013 (2011–2015)	2011 (2010–2013)
Treatment of cured infection
Ribavirin and pegylated interferon	85 (69.7%)	63 (67.2%)	22 (78.6%)
DAA ± ribavirin	27 (22.1%)	25 (26.6%)	2 (7.1%)
No treatment (spontaneous clearance)	10 (8.2%)	6 (6.4%)	4 (14.3%)
Median time from HCV reinfection to treatment initiation, months	6.5 (4.4–10.1)	6.7 (4.5–14.2)	5.7 (3.7–7.6)
HCV genotype of cured infection
1	80 (65.6%)	62 (66.0%)	18 (64.3%)
2	10 (8.2%)	8 (8.5%)	2 (7.1%)
3	6 (4.9%)	5 (5.3%)	1 (3.6%)
4	17 (13.9%)	13 (13.8%)	4 (14.3%)
Unknown	9 (7.4%)	6 (6.4%)	3 (10.7%)
FOLLOW-UP
Total follow-up time, years	295.5	229.7	65.7
Median follow-up time, years	1.4 (0.5–3.8)	1.2 (0.5–3.7)	1.6 (0.8–4.2)
Median time between RNA measurements, monthsb	5.0 (3.0–6.0)	4.9 (2.9–5.9)	5.4 (3.1–6.0)
Maximum ALT (U/L)a	32 (23–62)	28 (22–42)	88 (47–133)
Genotype switch at reinfection (possible reinfections excluded)c
Gt 1 –> Gt 1, different clade			12
Gt 1 –> Gt 3			1
Gt 1 –> Gt 4			4
Gt 2 –> Gt 1			2
Gt 3 –> Gt 4			1
Gt 4 –> Gt 1			2

Abbreviations: ALT, alanine aminotransferase; cART, combination antiretroviral therapy; DAA, direct-acting antiviral; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IQR, interquartile range; MSM, men who have sex with men; MOSAIC, MSM Observational Study of Acute Infection with hepatitis C.

^a2 missing values.

^bCalculated as the median of the median time per person.

^c4 missing values.

Incidence of HCV Reinfection

The median follow-up time for the 122 MSM included was 1.4 years (interquartile range [IQR] 0.5–3.8), totaling 295.5 person-years. A total of 34 reinfections occurred among 28 MSM. The IR of HCV reinfection overall was 11.5/100 person-years (95% CI 8.2–16.1). The IR for first reinfection was 8.0/100 person-years (95% CI 5.2–12.2) and for second, third, or fourth HCV reinfection 38.3/100 person-years (95% CI 18.3–80.4). When excluding possible reinfections (n = 8), the overall reinfection IR was 9.1/100 person-years (95% CI 6.2–13.3). The cumulative incidence of first reinfection since end of treatment of spontaneous clearance of previous infection is depicted in Figure 1 and was 25% (95% CI 17–36) after 2.5 years and 40% (95% CI 28–54) after 5 years. Among those with reinfection, median time to reinfection was 1.3 years (IQR 0.6–2.7).

Figure 1.

Cumulative incidence including 95% confidence interval of HCV reinfection among 122 HIV-positive MSM participating in the MOSAIC study, the Netherlands. Cumulative incidence was calculated using the Kaplan-Meier method. Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus; MOSAIC, MSM Observational Study of Acute Infection with hepatitis C; MSM, men who have sex with men.

Risk Factors for HCV Reinfection

In total, 117 MSM were included in risk factor analysis for whom questionnaire data around the time of 1 (n = 18), 2 (n = 1), or 3 reinfection(s) (n = 1) were available. Five MSM with HCV reinfection had their first visit with questionnaire data more than 1 month after reinfection diagnosis and were thus excluded. Table 2 shows the characteristics at the last follow-up visit for those without reinfection (n = 97, 3 more than in the incidence analysis because these cases were censored before reinfection occurred) and at the closest visit to first reinfection diagnosis (with available data) for those with ≥1 reinfections (n = 20). As shown in Table 2, HCV reinfection was associated with nadir CD4 cell count <200 cells/mm³ (posterior-HR 2.22, 95% CrI 1.05–4.81), recent CD4 cell count <500 cells/mm³ (posterior-HR 3.60, 95% CrI 1.73–7.64), receptive condomless anal intercourse (posterior-HR 4.27, 95% CrI 1.86–9.78), sharing of sex toys (posterior-HR 4.91, 95% CrI 2.27–10.31), group sex (posterior-HR 2.80, 95% CrI 1.33–5.98), anal rinsing before sex (posterior-HR 2.47, 95% CrI 1.14–5.43), and ≥10 casual sex partners in the past 6 months (posterior-HR 2.81, 95% CrI 1.26–6.50). The proportion of MSM reporting these determinants did not differ between the first and last visit included in the analyses.

Table 2.

Characteristics and Risk Behavior Reported at End of Follow-up or at Visit Prior to Hepatitis C Virus (HCV) Reinfection, and Prior and Posterior Estimates of Risk Factors for Reinfection

	Not Reinfected (N = 97), median (IQR) or number (%)	Reinfected (N = 20), median (IQR) or number (%)	Na	PYb	Prior HR (95% CrI)	Posterior HR (95% CrI)
Sociodemographic characteristics
Age, years	48.1 (42.2–52.1)	43.4 (39.6–47.3)
Age, categories
<40 years	20 (20.6%)	6 (30%)	6	36.9	reference	reference
40–49 years	41 (42.3%)	11 (55%)	14	100.4	1.00 (.25–4.00)	1.81 (.84–4.22)
≥50 years	36 (37.1%)	3 (15%)	3	71.5	1.00 (.25–4.00)	0.71 (.27–1.74)
HIV clinical characteristics
Nadir CD4 cell count <200 cells/mm3 c	28 (29.5%)	9 (45.0%)	11	60.4	1.00 (.25–4.00)	2.22 (1.05–4.81)
CD4 cell count (cells/mm3)	660 (490–870)	480 (399–564)
CD4 cell count <500 (cells/mm3)	26 (26.8%)	10 (50.0%)	12	49.2	1.50 (.38–6.00)	3.60 (1.73–7.64)
On cART	93 (95.9%)	19 (95.0%)
Detectable HIV RNA (≥50 copies/mL)	7 (7.2%)	3 (15.0%)	3	14.1	2.00 (.50–8.00)	2.23 (.79–5.30)
HCV clinical characteristics
Spontaneous clearance	6 (6.2%)	4 (20.0%)	5	22.2	1.00 (.25–4.00)	1.92 (.74–4.40)
Treated with DAAs	25 (27.5%)	1 (6.3%)	1	10.1	1.50 (.38–6.00)	1.41 (.41–4.00)
Treated for HCV >6 months after HCV infection	50 (55.0%)	9 (56.3%)	10	91.0	0.69 (.17–2.70)	1.50 (.66–3.38)
Sexual behavior
Receptive condomless anal intercourse	52 (53.6%)	17 (85.0%)	19	121.4	2.00 (.50–8.00)	4.27 (1.86–9.78)
Fisting without gloves	20 (20.6%)	7 (35.0%)	8	56.7	2.00 (.50–8.00)	1.95 (.88–4.03)
Sharing of sex toys	8 (8.3%)	8 (40.0%)	10	24.3	1.50 (.38–6.00)	4.91 (2.27–10.31)
Group sexd,e	43 (44.8%)	14 (70.0%)	15	94.4	1.50 (.38–6.00)	2.80 (1.33–5.98)
Anal rinsing before sex	57 (58.8%)	16 (80.0%)	17	131.8	1.50 (.38–6.00)	2.47 (1.14–5.43)
Rectal bleeding during sex	13 (13.4%)	6 (30.0%)	6	33.6	1.50 (.38–6.00)	2.03 (.86–4.39)
Number of casual sex partners
No casual sex partners	35 (36.0%)	2 (10.0%)	4	62.1	reference	reference
<10	31 (32.0%)	7 (35.0%)	7	64.3	1.50 (.38–6.00)	2.06 (.87–4.84)
≥10	31 (32.0%)	11 (55.0%)	12	82.4	1.50 (.38–6.00)	2.81 (1.26–6.50)
Drug use
Injecting drug use	6 (6.2%)	3 (15.0%)	3	17.0	2.00 (.50–8.00)	2.02 (.74–4.84)
Sharing of needles	0	0
Chemsexd,f	62 (64.6%)	14 (70.0%)	15	137.0	1.50 (.38–6.00)	1.71 (.79–3.69)
Sharing of straws when nasally administered drugs used	19 (19.6%)	2 (10.0%)	2	34.1	1.50 (.38–6.00)	0.90 (.34–2.25)
Sexually transmitted infections
Syphilis, genital herpes, or LGV	14 (14.4%)	3 (15.0%)	4	22.4	1.50 (.38–6.00)	1.90 (.72–4.37)
Syphilis	9 (9.3%)	3 (15.0%)	3	16.4	2.00 (.50–8.00)	2.05 (.77–4.82)

Abbreviations: cART, combination antiretroviral therapy; CrI, credible interval; DAAs, direct-acting antivirals; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HR, hazard ratio; IQR, interquartile range; LGV, lymphogranuloma venereum; MSM, men who have sex with men; PY, person-years.

^aNumber of reinfections with a given, time-updated risk factor (23 reinfections in total)

^bApplies only to those a risk for reinfection with a given, time-updated risk factor. Total person-years were 208.8.

^c2 missing values after imputation from subsequent visit.

^d1 missing value after imputation from subsequent visit.

^eSex with 2 or more partners.

^fSex while use of any of the following drugs: cocaine, MDMA (3,4-methyl-enedioxy-methamphetamine), ketamine, GHB (γ-hydroxybutyric acid)/GBL (γ-butyrolactone), amphetamine or methamphetamine.

Sensitivity Analyses

First, using noninformative priors, recent CD4 cell count <500 cells/mm³, receptive condomless anal intercourse, and sharing of sex toys were still associated with HCV reinfection but with increased uncertainty (ie, wider 95% CrI). In this analysis, the posterior HRs for nadir CD4 cell count <200 cells/mm³, group sex, anal rinsing, and ≥10 casual sex partners included 1 and age above 50 years became associated with a decreased risk of HCV reinfection (posterior-HR 0.25, 95%CrI .05–.93). Second, using a lower prior-HR for age above 50 years and higher prior-HR for HCV treatment initiation >6 months after HCV infection and rectal bleeding did not lead to any changes when compared to the main analysis. Third, when risk factor analysis was restricted to those at risk for first reinfection, the same risk factors were identified, except for nadir CD4 cell count <200 cells/mm³. When risk factor analysis was restricted to visits without missing data, nadir CD4 cell count <200 cells/mm³ and having ≥10 casual sex partners were no longer associated. Results of sensitivity analyses are shown in Supplementary Table 3.

DISCUSSION

In this study of 122 HIV-positive MSM, we assessed the incidence and risk factors for HCV reinfection following HCV spontaneous clearance or successful treatment. During a median follow-up of 1.4 years, we found an HCV reinfection incidence of 11.5/100 person-years. Using models adapted to the few numbers of HCV reinfections in this cohort, HCV reinfection was associated with receptive condomless anal intercourse, sharing of sex toys, group sex, anal rinsing before sex, ≥10 casual sex partners, nadir CD4 cell count <200 cells/mm³, and recent CD4 cell count <500 cells/mm³. To date, our study is the first to our knowledge that provides an assessment of behavioral risk factors for HCV reinfection specifically among HIV-positive MSM.

The identified risk factors are comparable to those associated with initial HCV infection in a previous analysis of MOSAIC data [22] and in other studies [27–31], yet there are some noteworthy differences. In contrast to studies evaluating risk factors for initial infection, we did not find an association of injecting drug use (IDU) and sharing of straws when snorting drugs. This might be due to the successful implementation of prevention measures in the Netherlands, reflected by the fact that all MSM declaring recent IDU (n = 9) did not share needles, according to their questionnaire responses. In addition, men who have been infected with HCV might be more informed about the risk associated with sharing straws than those without HCV. In our previous study evaluating risk factors for primary HCV infection [22], other factors associated with initial HCV infection in multivariable analysis were fisting without gloves and ulcerative sexually transmitted infections (syphilis, genital herpes, or lymphogranuloma venereum) [22]. In the present study among MSM at risk for reinfection, we did not find any association between these variables and risk of reinfection. It could be speculated that reduction in some risk behaviors, namely, fisting without gloves, is 1 type of risk behavior that can be reduced after diagnosis of the first HCV infection. In contrast, other behaviors, such as receptive condomless anal intercourse and sharing of sex toys, both of which were associated with initial HCV infection and reinfection, might be more difficult to change. Nadir CD4 cell count <200 cells/mm³ and CD4 cell count <500 cells/mm³ were associated with HCV reinfection and were also found to be associated with initial HCV infection [22, 27, 28]. Furthermore, several longitudinal studies have shown a temporary decline in CD4 cell counts after acute HCV infection [32, 33]. However, the clinical implications of this finding need to be further elucidated.

The overall IR of 11.5/100 person-years observed in this study is slightly higher than that found in studies among HIV-positive MSM elsewhere [6–15, 17]. Although reinfection rates might differ between regions, we allowed multiple reinfections per MSM in our estimate. When restricting analysis to the incidence of first HCV reinfection only, the IR was indeed lower (8.0/100 person-years). Furthermore, median time between RNA measurements was 5.0 months in our study, whereas the frequency of HCV RNA testing and hence the rate of reinfection might be lower in other studies [34]. In line with previous studies [6, 7], we found an even higher incidence for multiple HCV reinfections. This suggests that the HCV epidemic may be partly driven by a small group of high-risk MSM and highlights the need for close monitoring of these MSM (eg, via frequent HCV RNA testing) for timely detection of subsequent reinfection(s). Real-time phylogenetic analysis could be used to identify whether these infections derived from external introductions or ongoing transmission within existing local clusters. Tracing and testing of sex partners and networks of these MSM is of high importance to identify and treat MSM unaware of their HCV infection to halt onward HCV transmission.

Our study has some limitations. First, those with a possible reinfection were not sequenced for confirmation. However, the median time between end of treatment and estimated date of reinfection was 1.3 years and late relapses 24 weeks after end of treatment is considered rare [35]. Second, due to a small number of HCV reinfections, we were unable to perform multivariable analysis. Larger studies would be more ideal in assessing the combinations of multiple risk behaviors leading to HCV reinfection. Third, due to only 10.1 person-years of follow-up among MSM who were successfully treated with DAAs, we were unable to draw conclusions about whether the HCV reinfection rate might be higher in the DAA era.

In conclusion, incidence of HCV reinfection among HIV-positive MSM was very high, and we showed that sexual risk behavior was associated with HCV reinfection, highlighting the need for effective interventions aimed at reducing risk behavior and preventing reinfection among HIV-positive MSM. The risk factors found in this study could aid development of such interventions and could help clinicians identify patients at high risk for HCV reinfection who should be frequently monitored with HCV RNA testing.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Study group. The collaborators of the MOSAIC study are H. van Eden, J.T.M. van der Meer, R. Molenkamp, F. Pijnappel, H.W. Reesink, J. Schinkel, G.S. Steba, M. van der Valk (Amsterdam UMC, Academic Medical Centre of the University of Amsterdam, Amsterdam, the Netherlands); G.E.L. van den Berk, K. Brinkman, I. Hooijenga, D. Kwa, N. van der Meché, A. Toonen, D. Vos (OLVG Hospital, Amsterdam, the Netherlands); M. van Broekhuizen, F.N. Lauw, J.W. Mulder (MC Slotervaart, Amsterdam, the Netherlands); J.E. Arends, A. van Kessel, B. Silvius, M. Versloot (University Medical Center, Utrecht, the Netherlands); A. Boonstra, B.J.A. Rijnders (Erasmus Medical Center, Rotterdam, the Netherlands); W. Brokking, A. van Eeden, L. Elsenburg, H.E. Nobel (DC Clinics, Amsterdam, the Netherlands); T.J.W. van de Laar (Sanquin Blood Supply, Amsterdam, the Netherlands); C. Smit (Stichting HIV Monitoring, Amsterdam, the Netherlands); A.M. Newsum, M. Prins, W. van der Veldt (Public Health Service of Amsterdam, Amsterdam, the Netherlands).

Author contributions. A. N. contributed to the conception and design of the work, performed data management, data analysis, and drafted the manuscript. A. B. and A. M. contributed to the conception and design of the work and analysis of data. J. S., M. V., K. B., A. E., F. L., B. R., T. L., and J. A. contributed to the conception and design of the work and acquisition of data. C. S. contributed to data management. A. N., M. K., and M. P. assigned the priors for the statistical analysis. M. P. is the principal investigator of the MOSAIC study and contributed substantially to the conception and design of the work and interpretation of data. All authors critically revised the manuscript, and all approved the final version.

Acknowledgments. The authors thank all participants of the MOSAIC study. In addition the authors would like to thank M. Mutschelknauss for her contribution to the data collection, and L. May and G.R. Visser for their contribution to the data management.

Financial support. This work was supported by the “Aidsfonds” Netherlands (grant numbers 2008.026, 2013.037 to A. N., M. P., and the MOSAIC study) and the Netherlands Organization for Health Research and Development (ZonMw) (grant number 522004006 to M. K. and M.P.).

Potential conflicts of interest. J. S.’s institution has received research support and consultancy fees from Gilead, and a speakers fee from Janssen Pharmaceuticals, independent from the submitted work. M. P.’s institution has received speakers fees and independent scientific support from Gilead Sciences, Roche, MSD, and Abbvie, outside the submitted work. M. V.’s institution has received speakers fees from Abbvie, Bristol-Myers-Squibb, Gilead, Johnson & Johnson, MSD, and ViiV outside the submitted work and research grant from Abbvie, Gilead, Johnson&Johnson, and Merck Sharp Dome. K. B. has served on (inter)national advisory boards for Gilead, ViiV, Janssen and MSD outside the submitted work. B. R. has received grants from MSD and Gilead Sciences, and participated in advisory boards and received travel support from MSD, Janssen-Cilag, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and ViiV Healthcare, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.