A Phylogenetic Analysis of Hepatitis C Virus Transmission, Relapse, and Reinfection Among People Who Inject Drugs Receiving Opioid Agonist Therapy

Abstract

Background: Understanding hepatitis C virus (HCV) transmission among people who inject drugs (PWID) is essential for HCV elimination. We aimed to differentiate reinfections from treatment failures and to identify transmission linkages and associated factors in a cohort of PWID receiving opioid agonist therapy (OAT).

Methods: We analyzed baseline and follow-up specimens from 150 PWID from 3 OAT clinics in the Bronx, New York. Next-generation sequencing data from the hypervariable region 1 of HCV were analyzed using Global Hepatitis Outbreak and Surveillance Technology.

Results: There were 3 transmission linkages between study participants. Sustained virologic response (SVR) was not achieved in 9 participants: 7 had follow-up specimens with similar sequences to baseline, and 2 died. In 4 additional participants, SVR was achieved but the participants were viremic at later follow-up: 2 were reinfected with different strains, 1 had a late treatment failure, and 1 was transiently viremic 17 months after treatment. All transmission linkages were from the same OAT clinic and involved spousal or common-law partnerships.

Conclusion: This study highlights the use of next-generation sequencing as an important tool for identifying viral transmission and to help distinguish relapse and reinfection among PWID. Results reinforce the need for harm reduction interventions among couples and those who report ongoing risk factors after SVR.

Keywords: HCV; IDU; OAT; PWID; hepatitis C; next generation sequencing; phylogenetic; transmission network.

Figure 1.

Radial phylogram showing all hepatitis C virus (HCV) genotype 1a (n = 128; n = 3622 haplotypes) and genotype 1b (n = 22; n = 602 haplotypes) isolates at baseline, with color coding to indicate opioid treatment program center.

Figure 2.

Transmission clusters identified using Global Hepatitis Outbreak and Surveillance Technology (GHOST). A, Blue circles indicate participants not related to anyone else in the network. The size of the circle is proportional to the number of different haplotypes found in the participants. Connected circles of the same color represent follow-up specimens from the same participants or transmission if they link different participants.. Two pairs were linked by transmission at baseline (pairs 1014-1026 and 2022-2033). B, Baseline transmission cluster of participants 1014 and 1026 (n = 449 haplotypes; frequency, >2). C, Baseline transmission cluster of participants 2022 and 2033 (n = 449 haplotypes; frequency, >5).

Figure 3.

Phylogenetic trees of hepatitis C virus (HCV) hypervariable region 1 variants sampled at baseline and follow-up time-points from participants in the PREVAIL in whom treatment failed. Abbreviations: BL, baseline; EOT, end of treatment; PT4, posttreatment week 4; PT12, posttreatment week 12; PT24, posttreatment week 24; TW4, treatment week 4. A, HCV genotype 1a (participants 1024, 1035, 1046, 1080, 2009, and 2020) (n = 795 haplotypes; frequency, >5). B, HCV genotype 1b (participant 1021) (n = 117 haplotypes; frequency, >10). C, HCV genotype 1a (participant 2020 (n = 409 haplotypes; frequency, >2). Arrow indicates a haplotype present at baseline at low frequency. D, Participant 2009. The major haplotypes at EOT and PT4 are identical (n = 730 haplotypes; frequency, >2).

Figure 3.

Phylogenetic trees of hepatitis C virus (HCV) hypervariable region 1 variants sampled at baseline and follow-up time-points from participants in the PREVAIL in whom treatment failed. Abbreviations: BL, baseline; EOT, end of treatment; PT4, posttreatment week 4; PT12, posttreatment week 12; PT24, posttreatment week 24; TW4, treatment week 4. A, HCV genotype 1a (participants 1024, 1035, 1046, 1080, 2009, and 2020) (n = 795 haplotypes; frequency, >5). B, HCV genotype 1b (participant 1021) (n = 117 haplotypes; frequency, >10). C, HCV genotype 1a (participant 2020 (n = 409 haplotypes; frequency, >2). Arrow indicates a haplotype present at baseline at low frequency. D, Participant 2009. The major haplotypes at EOT and PT4 are identical (n = 730 haplotypes; frequency, >2).

Figure 4.

Phylogenetic tree of hepatitis C virus hypervariable region 1 variants sampled from participant 1019 at different time points (n = 730 haplotypes; frequency, >5), in whom sofosbuvir-ribavirin treatment failed.

Figure 5.

Phylogenetic trees of hepatitis C virus (HCV) hypervariable region 1 (HVR1) variants sampled at baseline and follow-up time points from participants in the PREVAIL with probable reinfections. A, Phylogenetic tree of HCV HVR1 variants sampled from participant 2019 at different time points (n = 1018 haplotypes; frequency, >2). B, Phylogenetic tree of HCV HVR1 variants sampled from participants 1075 and 1046 at different time points, excluding the genotype 3a strain unrelated to any PREVAIL study members (n = 397 haplotypes; frequency, >2). Abbreviations: BL, baseline; EXT6, extended 6-month follow-up; EXT12, extended 12-month follow-up; PT4, posttreatment week 4; PT12, posttreatment week 12; PT24, posttreatment week 24.

Figure 5.

Phylogenetic trees of hepatitis C virus (HCV) hypervariable region 1 (HVR1) variants sampled at baseline and follow-up time points from participants in the PREVAIL with probable reinfections. A, Phylogenetic tree of HCV HVR1 variants sampled from participant 2019 at different time points (n = 1018 haplotypes; frequency, >2). B, Phylogenetic tree of HCV HVR1 variants sampled from participants 1075 and 1046 at different time points, excluding the genotype 3a strain unrelated to any PREVAIL study members (n = 397 haplotypes; frequency, >2). Abbreviations: BL, baseline; EXT6, extended 6-month follow-up; EXT12, extended 12-month follow-up; PT4, posttreatment week 4; PT12, posttreatment week 12; PT24, posttreatment week 24.