Meghan D. Morris

The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection.

Although 20%‐40% of persons with acute hepatitis C virus (HCV) infection demonstrate spontaneous clearance, the time course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had interleukin‐28 (IL28)B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1, and 7% had human immunodeficiency virus (HIV) coinfection. Twenty‐eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow‐up, spontaneous clearance occurred in 173 of 632, and at 1 year after infection, 25% (95% confidence interval [CI]: 21, 29) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4), with 34%, 67%, and 83% demonstrating clearance at 3, 6, and 12 months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex (adjusted hazards ratio [AHR]: 2.16; 95% CI: 1.48, 3.18), IL28B CC genotype (versus CT/TT; AHR, 2.26; 95% CI: 1.52, 3.34), and HCV genotype 1 (versus non‐genotype 1; AHR: 1.56; 95% CI: 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females, compared to males. Conclusions: Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex‐based differences in HCV control. (Hepatology 2014;58:109–120)

Patterns of hepatitis C virus RNA levels during acute infection: the InC3 study.

Background Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection. Methods Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study). Participants with well-characterized acute HCV infection (detected within three months post-infection and interval between the peak and subsequent HCV RNA levels≤120 days) were categorised by a priori-defined patterns of HCV RNA levels: i) spontaneous clearance, ii) partial viral control with persistence (≥1 log IU/mL decline in HCV RNA levels following peak) and iii) viral plateau with persistence (increase or <1 log IU/mL decline in HCV RNA levels following peak). Factors associated with HCV RNA patterns were assessed using multinomial logistic regression. Results Among 643 individuals with acute HCV, 162 with well-characterized acute HCV were identified: spontaneous clearance (32%), partial viral control with persistence (27%), and viral plateau with persistence (41%). HCV RNA levels reached a high viraemic phase within two months following infection, with higher levels in the spontaneous clearance and partial viral control groups, compared to the viral plateau group (median: 6.0, 6.2, 5.3 log IU/mL, respectively; P=0.018). In the two groups with persistence, Interferon lambda 3 (IFNL3) CC genotype was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95%CI: 1.08, 7.02). In the two groups with viral control, female sex was independently associated with spontaneous clearance compared to partial viral control (AOR: 2.86; 95%CI: 1.04, 7.83). Conclusions Among individuals with acute HCV, a spectrum of HCV RNA patterns is evident. IFNL3 CC genotype is associated with initial viral control, while female sex is associated with ultimate spontaneous clearance.

Cohort Profile: The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC3) Study

The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC(3)) Study is an international multi-cohort project of pooled biological and behavioural data from nine prospective cohorts of people who inject drugs (PWID). InC(3) brings together researchers from Australia, Canada, USA and the Netherlands with expertise in epidemiology, biostatistics, clinical and behavioural sciences, virology and immunology to investigate research questions relevant to hepatitis C virus (HCV) and HIV outcomes. InC(3) was established to: (i) create a merged multi-cohort study of pooled data from well-characterized cohorts of PWID with prospective data on HIV and HCV infections, with a particular focus on HCV; (ii) facilitate new studies not possible within individual cohorts; and (iii) bring together researchers across disciplines to answer a broad range of research questions. Study cohorts identify acute HCV cases through follow-up of high-risk HCV antibody-negative PWID or through clinical referral networks. To date, data from 1986 to 2010 have been received from all contributing cohorts, with 821 HCV-infected and 1216 HCV-uninfected participants (overall, n = 2037). Data collected include demographics, host genetics, HCV ribonucleic acid testing, alanine aminotransferase testing, HIV/hepatitis B virus testing, HCV therapy, loss to follow-up and mortality. Potential collaborators should contact the InC(3) PI Dr Kimberley Page (kPage@psg.ucsf.edu) for further information.

Hepatitis C virus reinfection and spontaneous clearance of reinfection - the InC3 study

BACKGROUND We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance. METHODS Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV in Injecting Cohorts study, which evaluated HCV infection outcomes among people who inject drugs. Participants with primary HCV infection were classified as having achieved viral suppression if they had negative results of at least 1 subsequent HCV RNA test. Those with positive results of an HCV RNA test following viral suppression were investigated for reinfection. Viral sequence analysis was used to identify reinfection (defined as detection of heterologous virus with no subsequent detection of the original viral strain). RESULTS Among 591 participants with acute primary HCV infection, 118 were investigated for reinfection. Twenty-eight participants were reinfected (12.3 cases/100 person-years; 95% confidence interval [CI], 8.5-17.8). Peak HCV RNA level was lower during reinfection than primary infection (P = .011). The proportion of individuals with reclearance 6 months after reinfection was 52% (95% CI, 33%-73%). After adjustment for study site, females with the IFNL4 (formerly IFNL3 and IL28B) rs12979860 CC genotype detected were more likely to have reclearance (hazard ratio, 4.16; 95% CI, 1.24-13.94; P = .021). CONCLUSIONS Sex and IFNL4 genotype are associated with spontaneous clearance after reinfection.

Higher risk of incident hepatitis C virus among young women who inject drugs compared with young men in association with sexual relationships: a prospective analysis from the UFO Study cohort

Background Female injection drug users (IDUs) may report differences in injection behaviours that put them at greater risk for hepatitis C virus (HCV). Few studies have examined these in association with HCV incidence. Methods Longitudinal data from a cohort of 417 HCV-uninfected IDU aged 30 or younger were analysed. Cox proportional hazards was used to model female sex as a predictor of new HCV infection. General estimating equation (GEE) analysis was used to model female sex as a predictor of HCV-associated risk behaviour prospectively. Results Women were significantly more likely than men to become infected with HCV during study follow-up (HR 1.4, p<0.05), and were also more likely than men to report high-risk injecting behaviours, especially in the context of sexual and injecting relationships. Sex differences in injecting behaviours appeared to explain the relationship between sex and HCV infection. Conclusions Young women’s riskier injection practices lead to their higher rates of HCV infection. Further study on the impact of intimate partnership on women’s risk behaviour is warranted.

Factors associated with pathways toward concurrent sex work and injection drug use among female sex workers who inject drugs in northern Mexico

AIMS To identify factors associated with time to initiation of (i) sex work prior to injecting drugs initiation; (ii) injection drug use prior to sex work initiation; and (iii) concurrent sex work and injection drug use (i.e. initiated at the same age) among female sex workers who currently inject drugs (FSW-IDU). DESIGN Parametric survival analysis of baseline data for time to initiation event. SETTING Tijuana and Ciudad Juarez situated on the Mexico-US border. PARTICIPANTS A total of 557 FSW-IDUs aged ≥18 years. MEASUREMENTS Interview-administered surveys assessing context of sex work and injection drug use initiation. FINDINGS Nearly half (n = 258) initiated sex work prior to beginning to inject, a third (n = 163) initiated injection first and a quarter (n = 136) initiated both sex work and injection drug use concurrently. Low education and living in Ciudad Juarez accelerated time to sex work initiation. Being from a southern Mexican state and initiating drug use with inhalants delayed the time to first injection drug use. Having an intimate partner encourage entry into sex work and first injecting drugs to deal with depression accelerated time to initiating sex work and injection concurrently. Early physical abuse accelerated time to initiating sex work and injection, and substantially accelerated time to initiation of both behaviors concurrently. CONCLUSIONS Among female sex workers who currently inject drugs in two Mexican-US border cities, nearly half appear to initiate sex work prior to beginning to inject, nearly one-third initiate injection drug use before beginning sex work and one-quarter initiate both behaviors concurrently. Predictors of these three trajectories differ, and this provides possible modifiable targets for prevention.

Geographic Differences in Temporal Incidence Trends of Hepatitis C Virus Infection Among People Who Inject Drugs: The InC3 Collaboration.

Summary Using longitudinal data from geographically diverse community cohorts, this study informs disease etiology by describing hepatitis C virus (HCV) incidence temporal trends and related exposure behaviors, highlighting the impact early and sustained harm reduction strategies can have on HCV trends.

Intimate injection partnerships are at elevated risk of high-risk injecting: a multi-level longitudinal study of HCV-serodiscordant injection partnerships in San Francisco, CA.

Background It is increasingly recognized that the risk for HIV and hepatitis C (HCV) transmission among people who inject drugs (PWID), such as syringe sharing, occurs in the context of relationships between (at least) two people. Evidence suggests that the risk associated with injection behavior varies with injection partner types. Methods We utilized longitudinal dyad-level data from a study of young PWID from San Francisco (2006 to 2013) to investigate the relationship-level factors influencing high-risk injecting within HCV-serodiscordant injection partners (i.e., individuals who injected together ≥5 times in the prior month). Utilizing data from 70 HCV-serodiscordant injection partnerships, we used generalized linear models to examine relationship-level predictors (i.e., partnership composition, partnership closeness, and partnership dynamics) of: (1) receptive syringe sharing (RSS); and (2) receptive cooker use (RCU), as reported by the HCV-negative injection partner. Results As reported by the “at-risk” HCV-negative injection partner, receptive syringe sharing (RSS) and receptive cooker use (RCU) were 19% and 33% at enrollment, and 11% and 12% over all visits (total follow-up time 55 person-years) resulting in 13 new HCV-infections (incidence rate: 23.8/100 person-years). Person-level factors, injection partnership composition, and partnership dynamics were not significantly associated with either RSS or RCU. Instead, intimate injection partnerships (those who lived together and were also in a sexual relationship) were independently associated with a 5-times greater risk of both RSS and a 7-times greater risk of RCU when compared to injecting only partnerships. Conclusion Our findings suggest a positive, and amplified effect of relationship factors on injecting drug risk behaviors among young PWID injection partnerships. The majority of interventions to reduce injection drug use related harms focus on individual-based education to increase drug use knowledge. Our findings support the need to expand harm reduction strategies to relationship-based messaging and interventions.

Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study

Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well‐defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC3 study). Individuals with persistent HCV and detectable HCV RNA during early chronic infection (one year [±4 months] postinfection) were included. Distribution of HCV RNA levels during early chronic infection was compared by selected host and virological factors. A total of 308 individuals were included. Median HCV RNA levels were significantly higher among males (vs females; 5.15 vs 4.74 log IU/mL; P < 0.01) and among individuals with HIV co‐infection (vs no HIV; 5.89 vs 4.86; P = 0.02). In adjusted logistic regression, male sex (vs female, adjusted odds ratio [AOR]: 1.93; 95%CI: 1.01, 3.69), interferon lambda 4 (IFNL4) rs12979860 CC genotype (vs TT/CT; AOR: 2.48; 95%CI: 1.42, 4.35), HIV co‐infection (vs no HIV; AOR: 3.27; 95%CI: 1.35, 7.93) and HCV genotype G2 (vs G3; AOR: 5.40; 95%CI: 1.63, 17.84) were independently associated with high HCV RNA levels (>5.6 log IU/mL = 400 000 IU/mL). In conclusion, this study demonstrated that IFNL4 rs12979860 CC genotype, male sex, HIV co‐infection and HCV genotype G2 are associated with high HCV RNA levels in early chronic infection. These factors exert their role as early as one year following infection.

Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort

Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high‐risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n = 161; pegylated interferon/ribavirin n = 76) (30% female, median age 35 years, 56% ever injected drugs, median duration of infection 6.2 months). Sixteen per cent (n = 38) were HIV/HCV co‐infected. SVR among those with HCV mono‐infection was 64% by intention to treat; SVR was 68% among HCV/HIV co‐infection. Independent predictors of SVR in HCV mono‐infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85–0.99, P = 0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI 1.13–4.56, P = 0.021), baseline HCV RNA <400 000 IU/mL (aOR 2.06, 95% CI 1.03–4.12, P = 0.041) and age ≥40 years (vs <30: aOR 2.92, 95% CI 1.31–6.49, P = 0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype‐1 infection. Interferon‐based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision‐making.