Abstract
High rates of sexually transmitted infection and reinfection with hepatitis C virus (HCV) have recently been reported in human immunodeficiency virus (HIV)-infected men who have sex with men and reinfection has also been described in monoinfected injecting drug users. The diagnosis of reinfection has traditionally been based on direct Sanger sequencing of samples pre- and posttreatment, but not on more sensitive deep sequencing techniques. We studied viral quasispecies dynamics in patients who failed standard of care therapy in a high-risk HIV-infected cohort of patients with early HCV infection to determine whether treatment failure was associated with reinfection or recrudescence of preexisting infection. Paired sequences (pre- and posttreatment) were analyzed. The HCV E2 hypervariable region-1 was amplified using nested reverse-transcription polymerase chain reaction (RT-PCR) with indexed genotype-specific primers and the same products were sequenced using both Sanger and 454 pyrosequencing approaches. Of 99 HIV-infected patients with acute HCV treated with 24-48 weeks of pegylated interferon alpha and ribavirin, 15 failed to achieve a sustained virological response (six relapsed, six had a null response, and three had a partial response). Using direct sequencing, 10/15 patients (66%) had evidence of a previously undetected strain posttreatment; in many studies, this is interpreted as reinfection. However, pyrosequencing revealed that 15/15 (100%) of patients had evidence of persisting infection; 6/15 (40%) patients had evidence of a previously undetected variant present in the posttreatment sample in addition to a variant that was detected at baseline. This could represent superinfection or a limitation of the sensitivity of pyrosequencing. Conclusion: In this high-risk group, the emergence of new viral strains following treatment failure is most commonly associated with emerging dominance of preexisting minority variants rather than reinfection. Superinfection may occur in this cohort but reinfection is overestimated by Sanger sequencing. (Hepatology 2015;61:88–97)
Highlights
High rates of sexually transmitted infection and reinfection with hepatitis C virus (HCV) have recently been reported in human immunodeficiency virus (HIV)-infected men who have sex with men and reinfection has been described in monoinfected injecting drug users
An increase in the incidence of acute HCV infection among HIV-infected men who have sex with men (MSM) in Europe, Australia, and the United States has led to a substantial number of Abbreviations: DAA, direct-acting antiviral; HCV, hepatitis C virus; HIV, human immunodeficiency virus; interferon alpha (IFN), interferon; MSM, men who have sex with men; RBV, ribavirin; Sustained virological response (SVR), sustained virological response
We have previously shown that HCV in HIV-infected MSM is commonly associated with the presence of multiple strains in individual infected patients (10% with multiple genotypes)
Summary
High rates of sexually transmitted infection and reinfection with hepatitis C virus (HCV) have recently been reported in human immunodeficiency virus (HIV)-infected men who have sex with men and reinfection has been described in monoinfected injecting drug users. 89 studies on this new public health problem.[4] Descriptions of HCV reinfection in this group have been widely reported but have not employed deep sequencing or detailed phylogenetic analysis.[5,6] We have previously shown that HCV in HIV-infected MSM is commonly associated with the presence of multiple strains in individual infected patients (10% with multiple genotypes). We used viral load monitoring and deep sequence analysis to dissect the different causes of treatment failure using pre- and posttreatment plasma samples taken from patients who failed standard of care therapy with 24-48 weeks of pegylated interferon alpha (IFN) and ribavirin (RBV).[7] Sustained virological response (SVR) rates are typically lower in this group (59-71%) than in HCV monoinfected patients (98%).[8,9] We used detailed phylogenetic analysis of pre- and posttreatment variants obtained using Sanger sequencing, clonal analysis, and next-generation sequencing (NGS) to differentiate relapse from reinfection
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