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Among injection drug users treated for hepatitis C virus (HCV) infection, rates of reinfection were high soon after sustained virologic response but decreased with longer follow-up, according to a secondary analysis of the randomized HERO trial.

Of 415 participants followed for up to 42 months, the overall reinfection rate was 11.4 per 100 person-years at risk (95% CI 8.7-14.7) over 518 person-years of follow-up, reported investigators led by Alain Litwin, MD, MPH, of the University of South Carolina School of Medicine in Greenville, in .

There was a significant decrease in incident reinfection, however, with increasing follow-up after sustained virologic response. The rate was 15.5 per 100 person-years during the first 6 months of follow-up, which fell to 4.3 per 100 person-years from 18 months to 3 years of follow-up (P=0.008).

"Our results reinforce previous reports showing that most reinfections occur within 24 weeks of sustained virologic response, emphasizing the need to offer effective interventions early to prevent reinfection," Litwin and colleagues wrote.

Reinfection rates more than doubled in those who tested positive for methamphetamine compared with those who did not (adjusted incidence rate ratio [aIRR] 2.41, 95% CI 1.22-4.76) and more than tripled in those who reported injection drug use within the preceding 3 months compared with those who did not have recent use (aIRR 3.33, 95% CI 1.86-5.97).

The higher rates of reinfection in this analysis compared with likely reflects the higher-risk population included in the HERO trial, Litwin's group said. Over time, the untreated HCV population will include a higher proportion of individuals who are harder to treat due to severe substance use disorder, polysubstance use, mental health and medical comorbidities, homelessness, lack of social support, and poor access to transportation. These characteristics were all common among HERO participants, they noted.

However, high rates of reinfection indicate that treatment is being accessed by high-risk populations, they added. This high-risk group is a final barrier to the goal of eliminating HCV infection; the reinfections are easily treatable with simple, accessible direct-acting antiviral regimens. "Thus, while minimizing HCV reinfection is an important healthcare objective, the occurrence of reinfections is also indicative that treatment is reaching high-risk populations," they explained.

"These data will inform public health strategies to achieve HCV elimination," the authors concluded, "and minimize reinfection through identification of high-risk behaviors and the implementation of appropriate interventions for PWID [people who inject drugs] who require more intensive or frequent follow-up and prompt retreatment."

In an , Marianne Martinello, MBBS, PhD, and Gail Matthews, MBChB, PhD, of the University of New South Wales in Sydney, Australia, pointed out that more than 2 million people in the U.S. -- predominantly injection drug users -- are living with HCV infection.

"The higher rate of reinfection in the HERO study should not be a cause for alarm," they wrote. "First, it must be acknowledged that HCV reinfection will occur as DAA [direct-acting antiviral] treatment scale-up expands, particularly among populations at highest risk of transmission."

While there may be an initial increase, reinfection incidence will fall as population-level HCV prevalence declines, they added. "A successful HCV elimination strategy must anticipate this, and both clinicians and policymakers should not be discouraged, but be prepared to push on incorporating surveillance, prevention, and management of reinfection in their approach."

Primary results from the HERO () trial, which compared the effectiveness of modified directly observed therapy and patient navigation at opioid treatment programs and community health centers from 2016 to 2018, showed no significant difference in sustained virologic response between the two treatment groups (73.9% vs 74.5%, P=0.35).

The secondary analysis, conducted in 2022, included 415 participants from the original trial with sustained virologic response after treatment with direct-acting antiviral therapy. Mean age was 44.7, and 72.8% were men. Overall, 72.8% reported recent injection drug use, 46.3% were living in unstable housing, and 75.4% had received recent methadone or buprenorphine for opioid use disorder.

Reinfection rates varied significantly across the included opioid treatment programs and community health centers, ranging from 2.9 per 100 person-years at risk (95% CI 0.1-16.3) to 25.2 per 100 person-years at risk (95% CI 15.6-38.5; P=0.006).

Limitations of the study included the predominantly urban setting and the significant differences in reinfection rates among the study sites, Litwin and team said, noting that more than one-third of reinfections were reported at a single site.

In addition, many of the participants lost to follow-up had characteristics associated with higher risk for reinfection, such as use of methadone for opioid use disorder. "Although the number of patients lost to follow-up was small, this overlap in characteristics suggests that patients who were lost to follow-up represented a cohort with higher-risk behaviors, potentially resulting in an underestimation of true reinfection rates," they explained.

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