Challenges and Controversies

Although it would be ideal to have an additional undetectable HCV RNA after the patient completed treatment, I would assume this patient has reinfection with the same genotype. He had an undetectable RNA at 12 weeks and the risk of viral relapse after 12 weeks is extremely rare. Although HCV reinfection among people who inject drugs (PWID) is not as common as initial infection among the general population, continued intravenous drug use is a known risk factor for reinfection. PWID found to be HCV reinfected should be offered re-treatment along with simultaneous harm reduction strategies to minimize future infection risk. Since the patient has reinfection, and not treatment failure, I would offer him the same treatment as a naive patient. Even though the patient has taken glecaprevir-pibrentasvir before, there is no reason to suspect that the newly acquired virus has mutations, since the virus has not seen the antiviral before. Although 12 weeks of sofosbuvir-velpatasvir is also an option for a naive patient without cirrhosis with genotype 1a, I would opt to treat someone with co-occuring substance use disorder with the shortest regimen possible to promote treatment completion.

In this case, the patient achieved an SVR12, defined as an undetectable HCV RNA at least 12 weeks following completion of therapy. The SVR12 is a robust surrogate for virologic cure. In a detailed molecular and phylogenetic analysis of 3,004 patients across 11 phase 3 clinical trials, only 5 patients (0.1%) who achieved SVR12 had evidence of a 'late relapse' with a phylogenetically similar virus (Sarrazin et al). This data suggests that clinicians should largely take a negative HCV RNA at the SVR12 timepoint to be a definitive 'cure', and interpret any subsequent viremia as most likely representing reinfection.
Active injection drug use does indeed predispose this patient to reinfection after achieving SVR12, with an estimated rate of this occurrence of roughly 6.2 per 100 person years according to a meta-analysis 36 studies (Hajarizadeh B et al). In people who are actively injecting drugs, the SVR12 timepoint represents an ideal moment to discuss the principles of harm reduction, including sharing resources on clean syringe exchange, buprenorphine programs, and overdose prevention. To be clear, this does not represent a reason to withhold treatment from these populations. Rather, treating people who inject drugs should be a priority of any HCV elimination effort, as one analysis suggested that ongoing transmission may exceed 20 additional individuals in the earl injecting career of a single person who is sharing needles (Magiorkinis et al). Treating and curing these patients not only will decrease onward transmission of HCV, but also offers numerous opportunities to offer other health and harm reduction interventions that may have lasting benefits at reducing overdose death, decreasing hazardous substance use, etc.
Because reinfection is likely to be with a distinct new virus, with a low likelihood of de novo anti-viral resistance retreatment, treatment can be undertaken as if the patient was treatment naive. Either SOF/VEL x 12 weeks or Gle/Pib x 8 weeks would be an option, but in this case, the patient has demonstrated that he tolerated, completed, and was already cured by an 8-week Gle/Pib regimen. Unless he brought to light any significant side effects or intolerances from the first treatment, I would retreat with Gle/Pib x 8 weeks with concomitant harm reduction counseling, offering of clean syringe services, and urge him to seek out a buprenorphine or other Medication-Assisted treatment (MAT) program.