Introduction

Hepatitis C virus (HCV) incidence is highest among younger, recent initiates to injection drug use in the United States (US) [1], and over the past decade infection has increased among younger people who inject drugs (PWID) in both urban and rural areas [2–4]. In studies that have prospectively studied HCV incidence, rates are markedly high; in a San Francisco cohort of young adult (age<30 years) PWID (UFO Study), HCV has hovered at 25/100 person-years observation (pyo) since 2002 [5, 6]. And, in rural Kentucky, incidence in PWID is estimated at 21.2/100 pyo (95% CI: 16.2, 27.7) (J. Havens, personal communication).

HCV infection is an important public health problem: over time, chronic infection leads to substantial liver disease, including cirrhosis and hepatocellular carcinoma, and HCV-associated mortality surpasses all other reportable infectious disease mortality in the US [7]. Temporally, in PWID, HCV infection almost always precedes HIV infection. For instance, reports of HCV foreshadowed the recent HIV outbreaks in Indiana [8, 9] and more recently in West Virginia and Massachusetts [10–13].

Multiple individual level exposures that increase risk for HCV are recognized including—the duration and frequency of injecting, sharing needles, syringes and injecting equipment, and female sex [5, 14–16]. Some researchers have suggested that younger injectors are more likely to acquire HCV infection from older injectors [17], especially young women [18], yet this has not been studied in quantitative analyses. The higher HCV prevalence observed in older PWID relative to younger PWID [19–21] could contribute to higher transmission rates from older to younger groups. PWID under age 35 have been shown to have higher injection related risk behavior relative to those older than 35 [20]. Medication for opioid use disorder and syringe service programs, which reduce the frequency and high risk of injecting and syringe sharing, have been shown to significantly reduce risk of HCV acquisition [22] including in young adult PWID [23]. But, social factors within injecting partnerships are also operative, amplifying both individual risk behaviors and subsequent infection risk [5, 24, 25]. Our group has studied injecting partnerships as an exposure variable in several epidemiological studies, defined broadly as “people whom you injected the most with- in the past month”, asked in order of first, second and third most frequent partners [5, 24, 25]. Injecting partners were not necessarily syringe sharing partners. The reasoning behind our use of the term “injecting partnerships” is that for a great majority of PWID, injecting drugs is a highly social activity not conducted in isolation [18, 26, 27]. Injecting partnerships are formed for various reasons, including for economic benefits, such as to share drugs and the associated costs [5, 28, 29], because of the risk environment (eg., safety), and for social resource and/or intimate and romantic reasons [30, 31]. Young adult PWID in overlapping injecting/sexual partnerships have five-fold higher odds of receptive needle sharing and more frequent injecting than PWID in injecting only partnerships [32]. In the UFO Study, both women and men who report injecting with sex partners relative to those who do not report these overlapping partnerships, have higher risk for HCV (adjusted Hazard Ratio (aHR) = 2.23; 95% CI, 1.9, 2.6) [24]. We also found that the smaller aged difference (< 5 years vs. ≥10 years) between injecting partners was associated five-fold higher odds of receptive needle sharing, a significant risk exposure for HCV [25]. Further, those that thought their partner was HCV-positive were significantly less likely to engage in receptive needle sharing with that partner, suggesting an avoidance of risk within injecting partnerships when HCV status was known, a potentially protective behavior. In this paper, due to accumulating HCV infections, we are able to follow up on these previous findings of behavioral outcomes higher injecting risk exposures found to be associated with age and lower risk behaviors associated with knowledge of partner’s status and examine associated HCV incidence outcomes. Because of these previous findings and the view of many that younger and more recent initiates have less knowledge about injecting safety and resources to reinforce risk reduction, we hypothesized that age-related injection partner mixing may be associated with HCV risk: young adult (<30 years old) injectors with younger injecting partners will have higher risk of HCV, and knowledge of partners’ serostatus may moderate this risk due to them taking necessary precautions. To test this we: (1) estimated incidence of HCV among young adult PWID by the age mix of their three most frequent injecting partners; and (2) examined effect modification by perceived knowledge of injecting partner’s HCV serostatus. The goal of this analyses is to better understand how age mixing and knowledge of injecting partners’ HCV status impacts HCV transmission and to inform prevention approaches to reduce acquisition and transmission of HCV among PWID.

Methods

Results

Between April 2003 and August 2018, a total of 2,486 people was screened, 930 (37.4%) met eligibility criteria and completed a baseline interview, of whom 710 (76%) were HCV negative (RNA and/or anti-HCV), and 522 (74%) had at least one follow-up interview. A total of 448 (85.8% of 522) participants reported on at least one to three injecting partnerships each, for a total of 986 injecting partnerships is included in this analysis. Of the 710 completing baseline interviews, those reporting having at least one partnership compared to those reporting no partnerships were significantly more likely to be female (31% vs. 21%, p = 0.04), inject heroin or heroin mixed with other drugs ‘most days’ (vs. methamphetamine or other drugs; (67% vs. 55%, p = 0.02), inject every day in the past month (38% vs. 16%, p<0.01), and attend syringe service programs (80% vs. 59%, p<0.01). Participants who remained in follow up (N = 522) vs. those who did not (N = 188), respectively, were older (median age = 24.0 vs. 23.1, p = <0.01), and more likely to have ever been tested for HCV (71.2% vs. 56.6%, p<0.01) and HIV (85.5% vs. 78.5%, p = 0.03), to attend syringe service programs (79.3% vs. 69.6%, p<0.01), to have received mental health services in the past 3 months (24.5% vs. 11.0%, p<0.01), to inject every day in the past month (38.1% vs. 24.1%; p<0.01), to use non-injected methamphetamine (64.8% vs. 54.3%, p = 0.01); and less likely have a AUDIT-C score indicative of probable alcohol dependence (12.5% vs. 24.4%, p<0.01).

Baseline characteristics of the sample at risk are shown in Table 1. Median age was 24.0 (IQR: 21.4, 26.4), just under one-third (29.2%) were women, 32.6% did not graduate high school. In the prior 3 months, 74.6% reported they were homeless or unstably housed, and 25.6% had been incarcerated. At baseline, prior to testing, 37.8% of participants did not know or had never been previously tested for HCV. The study sample reported a median 3.8 years of injecting (IQR: 1.7, 7.2). In the past month, median number of injecting partners reported was 4 (IQR 2, 10), 38.2% were daily injectors, and in the past 3 months: 81.5% reported injecting heroin or heroin mixed with other drugs, 30.3% reported receptive needle sharing, 61.7% shared ancillary equipment, and 44.1% reported injecting with 5 or more people. Median duration of follow-up in the analysis population was 10 months (IQR: 3.0–29.0 months).

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Table 1. Baseline demographic characteristics and recent injecting behaviors of hepatitis C virus (HCV) negative young injection drug users in San Francisco with ≥1 injecting partner (N = 448).

https://doi.org/10.1371/journal.pone.0226166.t001

HCV incidence (per 100 pyo) was higher in those whose injecting partners were all <30 years of age: 23.9 (95% CI: 18.8, 30.4), and in those with mixed-age injecting partnerships (28.5; 95% CI: 21.8, 37.1) compared those whose partners were ≥30 years of age (7.5; 95% CI: 4.8, 11.8). Among those who did not report any injecting partnerships, and who were excluded from the analysis, we observed 15 seroconversions an incidence rate of 16.2 (95%CI: 9.7, 26.8) per person year of observation.

Characteristics of the injecting partnerships and associations with HCV incidence are shown in Table 2. Over half (52.2%) of participants reported on three injecting partners: 44.9% reported that all of their injecting partners were <30 years old, and 38.6% that all of their injecting partners were HCV-negative. Most had at least one male partner (88.1%), and 37.0% had one or more injecting partners who were also sex partners. Less than a third (32%) of participants in this sample reported having only one injection partner. Knowledge of partners’ HCV status differed significantly by this indicator of monogamous injecting relationship: those with only one partner compared to those with multiple partners were significantly less likely to have a known HCV-positive partner (19.4% vs. 44.7%), or HCV-status unknown partners (30.9% vs. 41.8%) and more likely to inject only with HCV-negative partners (49.6% vs. 13.6%). In bivariable Cox regression analyses, compared to those whose partners were ≥30 years, HCV acquisition was associated with having all injecting partners <30 years (HR = 2.5: 95% CI: 1.5, 4.2) or a mix of partners both <&≥30 years (HR = 2.9: 95% CI: 1.7, 5.0). Compared to those whose partners were all HCV-negative, HCV acquisition was associated with having a mix of HCV-negative and HCV-unknown partners (HR = 2.0: 95% CI 1.2, 3.5) and having any HCV-positive partner (HR = 4.1: 95% CI: 2.4, 6.8). HCV acquisition was significantly associated with having ≥3 injection partners (vs. 1; HR = 3.6, 95% CI: 2.3, 5.6), having ≥2 male injecting partners (vs. 1; HR = 3.5, 95% CI: 1.8, 7.1), and reporting multiple partners of the opposite sex (HR: 2.0, 95CI: 1.3, 3.1) relative to no partners of the opposite sex. Receptive needle sharing and sharing ancillary equipment were both significantly associated with incident HCV in bivariate analyses. However HCV was not associated with having injecting partners who were also sex partners (Table 2), and not associated with the index partner’s age (HR: 1.0, 95% CI: 0.9, 1.0) or sex (HR: 0.8, 95% CI: 0.6, 1.2).

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Table 2. Injecting partnership characteristics^* and bivariate associations with HCV incidence.

https://doi.org/10.1371/journal.pone.0226166.t002

Multivariable analyses adjusting for sex and age of respondent, frequency of injecting, and number of partnerships are shown in Table 3. HCV acquisition was independently associated with having all injecting partners <30 years, knowledge that at least one partner was HCV-positive (adjusted HR (aHR) = 2.6, 95% CI: 1.3, 5.3), and with having mixed age partnerships (<&≥30 years) and knowledge that at least one partner was HCV-positive (aHR = 2.1, 95% CI: 1.0, 4.3). A significant interaction was found between partnership age mix and perceived knowledge of partners HCV status (p = 0.03). Fig 1 shows incidence rates by injecting age mix and knowledge of HCV serostatus group: the highest HCV incidence was in those whose injecting partners were <30 years of age and any partner was known to be HCV-positive, over five-fold higher than observed in those whose partners were all ≥30 years and any partner was known to be HCV-positive (Incidence Rate Ratio (IRR) = 5.9 (95% CI: 2.7, 13.2)).

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Fig 1. HCV incidence per 100/person years observation (and 95% Confidence Interval) among young people who inject drugs by injecting age and HCV serostatus partner group.

https://doi.org/10.1371/journal.pone.0226166.g001

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Table 3. Multivariable models of HCV incidence by injection partner mixing: Age and HCV serostatus and select characteristics in young adult PWID; n = 448^*.

https://doi.org/10.1371/journal.pone.0226166.t003

Discussion

In this study of HCV incidence in young injectors, rates of infection differed by injecting partner age and knowledge of HCV status of these partners. Those at lowest risk for HCV were those whose injecting partners were all older—over 30 years of age, including if they knew that at least one of these was HCV-positive. Although researchers have suggested that younger injectors are more likely to get HCV infection from older injectors, studies have not directly assessed this [17, 18]. Our study provides the first evidence that younger injectors injecting with persons of similar age are more likely to become infected with HCV, independent of other exposures including sex, injection frequency and equipment sharing. In a study of HCV phylogenetic clustering among PWID in Vancouver, Canada, younger age, HIV co-infection, HCV seroconversion and recent syringe borrowing were independently associated with membership in an HCV cluster [35], and in further examination of infections in pairs of clusters, researchers showed that viruses from 28 younger (<27 years) PWID were more likely to be closely related to viruses from other younger injectors, with fewer such events in older and younger injection pairs [36]. Examining the intersectional nature of social relationships for which injection drug use occurs within can substantially inform disease transmission patterns and inform control and prevention methods. Examining partner mixing is one approach to examine these risks and disease patterns [37]. Older adults have been shown to mix with their and all other age groups but younger adults do not–instead mixing more with younger adults [38, 39]. Collectively, these results extend our previous findings of higher exposure risk within pairs of younger PWID [25] and suggests that young PWID are at highest risk for forward transmission.

Risk of HCV acquisition is further impacted by perceived HCV status of injecting partners. Participants with younger injecting partners who also reported that some of those partners were HCV positive had over five-fold higher incidence of HCV relative to those in injecting relationships with older partners that included some partners with HCV infection. In previous analyses, young adult PWID had lower odds of reporting injection equipment sharing with HCV-positive partners relative to older PWID [25]. These updated data are consistent with those previously published; the proportion of respondents who report any receptive syringe sharing (22%) and any sharing ancillary equipment (70.4%) within injecting partnerships was similar to those previously published (23% and 64%, respectively). Our results suggest that protective seroadaptive behavior may vary with age. Younger injectors, notably those with shorter injecting careers acquire HCV very rapidly [1, 21], in association with higher risk injecting exposures [40]. We have previously reported that young adult PWID did not report reducing lending of previously used injecting equipment to others or ancillary equipment sharing after having been informed of their HCV infection following testing [41]. It is possible that the older partners are the ones who are engaged in more protective behaviors, resulting in protection for younger PWID. A study in San Diego found that accurate knowledge of HCV infection increased with age [42]. It is possible that younger injectors with older partners may be more likely to be injecting partner monogamous, thus limiting exposure to other HCV infected persons. Since HCV prevalence is higher in older injectors, these results suggest that behavioral factors, potentially seroadaptive behaviors, may be operational in reducing HCV incidence, as has been seen with HIV in MSM dyads [43]. Interpersonal dynamics that contribute toward how partners inject is associated with trust, intimacy and cooperation, which also contribute to perceived risk for infection [44]. These injecting related interpersonal dynamics may differ based on age differences in injecting partnerships. Further exploration to identify who and how these seroadaptive mechanisms can be harnessed for greater dissemination, potentially from older-younger to young-younger groups or in injecting dyads. Conversely, awareness of partner's HCV status may not influence injection decisions if HCV not considered a serious concern, or if HCV is thought to be unavoidable [45, 46]. There may be age differences in the perception of HCV infection as an expected consequence of injecting and how this is dealt with in partnerships [47]. All of these factors may also have contributed to the lack of association found between sexual partnerships and HCV infection outcomes, a result we found to be unusual given previous research shows that overlapping sexual/injecting partnerships have been shown to be associated with differential risk exposures for HCV infection [24, 31, 48]. The interpersonal dynamics influencing behaviors sexual relationships may be different within injecting partnerships [44]. We note that even when the partners are not sexual partners, there may be close and reciprocating social ties formed through the relational qualities of injecting together not captured by the term ‘sex partner’ that is likely to be associated with a heightened risk of unsafe injection practices. In a cohort of PWID in Baltimore, Smith et al, 2018 [49] examined the propensity of mixing patterns and found that age assortative patterns were more likely in association with sexual mixing compared to drug-sharing contacts and casual contacts. The lack of association between sexual partnerships reported may be due to collinearity with age mixing, and other factors that drive partner selection, such as limited pools of partners, housing or non-housing patterns, the length of time partners have known and have injected with each other, or the additional roles played by some partners who may supply drugs, or for newer initiates, assist them with injection. As our findings also show, risk can vary with knowledge of serostatus and it is possible that “riskier” behaviors occur in sex partnerships that are seroconcordant. As HCV testing and awareness increase, negotiated safety may also change.

In addition to behavioral and interpersonal factors, HCV infection dynamics may contribute to higher incidence within younger injecting partnerships [50]. The acute infection phase may contribute to increased incidence due to the long seronegative viremic window (approximately two months) [34], and high viremia during this phase of infection [51]. Since HCV screening is primarily conducted using antibody testing, those with newly acquired infection, (i.e. younger PWID), which is also mostly asymptomatic, do not know they are infected. If they are in a phase of high-risk injecting behavior, lack of knowledge of active infection could contribute to further transmission. Testing all PWID for HCV RNA has potential to better inform people about their risk and contribute to behavior change. Prompt HCV RNA diagnosis could contribute to counselling for risk reduction and disclosure within partnerships as well as discussions about HCV treatment. Modeling studies have suggested that HCV treatment for PWID [52], and their partners [53] may lead to substantial reductions in HCV prevalence and transmission. Targeting treatment to younger PWID in ‘treatment as prevention’ approaches—those at highest risk has potential to be efficient and have high impact prevention results–- similar to what has been shown in models of HCV vaccination strategies [54].

This study has some potential limitations. Participants may misreport partnership characteristics in association with recall or social desirability bias. However, as risk would tend to be underreported, this would bias results toward the null. It should be noted that the addition of perceived HCV status to the model of HCV incidence results in large confidence intervals showing that this measure is unstable. These findings may not necessarily be generalizable to cohorts and networks of persons who inject drugs who live in other communities at risk. In Vietnam older injectors (30–39 years old) had higher injection equipment sharing patterns compared to other groups [49]. Social mixing, including injecting relationships may differ in association with race/ethnicity or other factors not seen in this primarily white cohort in San Francisco [55]. We did not measure duration, location or contact frequency within these injecting partnerships, but determined whether the relationship involved injecting. We also did not specifically restrict our analyses to age mixing within equipment sharing partnerships, and these results do not denote a transmission probability. We note that the including partnerships that may potentially have excluded equipment sharing results in a bias toward the null in terms of risk of HCV incidence. We further note we queried participants about the three partners with whom he/she had injected the most or with whom they spent the most time in the prior month, but some may have had more than three partners. Strengths of the study include repeated and accurate ascertainment of HCV incidence, including antibody and RNA testing.

In summary, findings from this study have important potential to inform new interventional approaches for HCV prevention in young PWID, which is critical given the expanding HCV epidemic. In addition to expanding testing to identify and promote treatment of HCV infection among PWID, promoting knowledge of protective behaviors, could be disseminated by older PWID. Note that with status quo in San Francisco, where there are significant programmatic prevention efforts aimed at PWID [56], HCV incidence has been stable and high in this young adult cohort. Younger people are the most challenging to retain in care and prevention, including treatment for opioid use disorder OUD [57, 58], using medications are more likely to be retained in care than those who receive only behavioral intervention [59]. Effective OUD treatment can substantively reduce HCV incidence [22], making the to test interventions that promote young people’s retention in these programs a priority. Given the widespread increases in HCV nationally in young adult PWID, new prevention interventions aimed at this younger population that address the social and cultural contexts of injecting partnerships should be tested.

Acknowledgments

The authors would like to express our gratitude to the UFO Study field team for their dedication to the research. The authors would like to acknowledge the gracious and considerate involvement of the following organizations who supported the study and the participants: San Francisco Department of Public Health, Homeless Youth Alliance, San Francisco Community Clinic Consortium Street Outreach Services, and San Francisco AIDS Foundation.