HIV HCV coinfection: Reasons for HCV Tx failure

Posted on April 13, 2015

New study suggests that HCV reinfection is not the reason for HCV treatment failure in sexually active HIV-infected patients with acute HCV

HIV-infected patients with acute HCV (HIV HCV coinfection) are likely to be at high risk of reexposure and therefore the presence of switching genotype or viral rebound following HCV therapy, indicating treatment failure, is often assumed to be secondary to reinfection. HCV reinfection is also thought to be a possible reason for treatment failure in monoinfected injecting drug users. Acute HCV infection is increasing in incidence among HIV-infected men who have sex with men (MSM) in Europe, Australia, and the United States, which necessitates an understanding of the extent to which HCV reinfection may contribute to the likelihood of HCV treatment failure, especially as sustained virological response rates are typically lower in HIV/HCV coinfected patients (59-71%) than in HCV monoinfected patients (98%).

Tamer Abdelrahman and colleagues recently published a study of HCV infection and reinfection in the setting of antiviral treatment in HIV-infected MSM (Abdelrahman T et al. Hepatology. 2015 Jan;61(1):88-97). The diagnosis of reinfection has traditionally been based on direct Sanger sequencing of samples pre- and posttreatment. More sensitive, deep sequencing techniques were employed in this study based on the hypothesis that reinfection rates following treatment may be overestimated by standard sequencing techniques due to a lack of detection of varying dominance of minority variant strains present at the onset of infection.

Of 99 patients with HIV treated for acute HCV infection between 2005 and 2012 in a single medical center in the UK, 15 patients failed to respond to standard of care treatment with 24-48 weeks of pegylated interferon alpha and ribavirin. Pre- and posttreatment plasma samples from these 15 patients were taken for analysis:

  • Standard direct Sanger sequencing revealed that 10 of these 15 patients (66%) had evidence of a previously undetected strain posttreatment; in many studies, this would be interpreted as reinfection.
  • In contract, deep sequencing techniques revealed that preexisting HCV strains were present in all 15 patients sampled following treatment failure. Six of these patients also had evidence of a previously undetected HCV variant in addition to a variant that was detected at baseline. This could represent superinfection.
  • Pre-treatment, all 15 patients had evidence of multiple strain infection with 2-6 variants of genotype 1a. Seven patients had evidence of mixed subtype or genotype infection at baseline; 6 patients had two subtypes (1a and 1b) and 1 patient had a mixed genotype infection (1a and 4d). The detection of multiple viral strains at a single pretreatment time-point in patients with acute HCV could be the result of simultaneous transmission, or superinfection within a short timeframe.
  • Minority strains that emerged following therapy ranged from 3% to 13% of the viral population in pretreatment samples, and reached up to 75-100% of the total viral population in posttreatment samples

Although a dominant HCV variant was present in most samples, mixed infection was present both pre- and post-treatment in the majority of patients, and variation in quasispecies composition was common over time, suggesting that certain strains may have been positively selected during treatment. This study suggests that clearance and reinfection is not the commonest mechanism of treatment failure in HIV-infected MSM, and reinfection is typically overestimated by direct Sanger sequencing.

 


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