Hepatitis C Virus (HCV) Quasispecies Complexity and Selection in HCV/HIV-Coinfected Subjects Treated with Interferon-Based Regimens

ArticleinThe Journal of Infectious Diseases 201(5):712-9 · March 2010with11 Reads
DOI: 10.1086/650490 · Source: PubMed
Abstract
Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) has emerged as a major cause of morbidity and mortality due to liver disease. Interferon-based therapy response rates have been disappointingly low. Baseline HCV complexity and the relationship between complexity and viral kinetic parameters has not been well described in HCV/HIV-coinfected subjects. A subset of patients enrolled in the AIDS Clinical Trials Group 5071 trial underwent sampling to evaluate viral kinetics and changes in HCV complexity. Early kinetic parameters, baseline complexity, and treatment outcomes--including rapid viral response (RVR), early viral response (EVR), and sustained viral response (SVR)--were evaluated. HCV-monoinfected subjects were matched to HCV/HIV-coinfected subjects. Baseline complexity was determined in 108 HCV/HIV-coinfected subjects and in 13 HCV-monoinfected control subjects. Quasispecies complexity was a mean of 2.24 bands for HCV/HIV-coinfected subjects and a mean of 1.90 bands for HCV-monoinfected subjects (P = .14). Lower baseline complexity was associated with EVR (P = .04) and approached statistical significance for SVR. In patients who underwent viral kinetic modeling, a decrease in complexity was associated with RVR (P = .03) and was independent of the correlation between first-phase viral decline efficiency and RVR. Baseline HCV complexity is an independent predictor of EVR in HCV/HIV-coinfected subjects. A decrease in complexity occurs by 4 weeks after the initiation of interferon-based therapy and is associated with RVR. These findings may enhance the predictive modeling of treatment outcome in HCV/HIV-coinfected patients.
    • "Nonetheless, the mode of HDV genome replication (RNA pol-II) and editing (ADAR1) by host enzymes, with lower error rates than with viral polymerases, suggests that HDV complexity might be lower than that of viruses replicating with their own polymerases without proofreading activity. However, the 6 indices selected to describe quasispecies complexity according to incidence, abundance, and functionality show that HDV complexity is similar to or higher than that of other RNA viruses [17,41,42] despite its particular mode of replication. In addition , we found that HDV quasispecies complexity was significantly lower when the amber/W codon was excluded from the analysis, suggesting that this codon may represent an artifact in the assessment of the HDV complexity. "
    [Show abstract] [Hide abstract] ABSTRACT: Chronic HDV infection can cause a severe form of viral hepatitis for which there is no specific treatment. Characterization of the hepatitis B or C viral quasispecies has provided insight into treatment failure and disease recurrence following liver transplantation, has proven useful to understand hepatitis B e antigen seroconversion, and has helped to predict whether hepatitis C infection will resolve or become chronic. It is likely that characterization of the hepatitis delta virus (HDV) quasispecies will ultimately have similar value for the management of this infection. This study sought to determine the RNA evolution rates in serum of chronic hepatitis delta (CHD) treatment-naïve patients, using next-generation sequencing methods. The region selected for study encompassed nucleotide positions 910 to 1270 of the genome and included the amber/W codon. Amber/W is a substrate of the editing process by the ADAR1 host enzyme and is essential for encoding the 2 delta antigens (HDAg). The amber codon encodes the small (unedited) HDAg form and the W codon the large (edited) HDAg form. The evolution rate was analyzed taking into account the time elapsed between samples, the percentage of unedited and edited genomes, and the complexity of the viral population. The longitudinal studies included 29 sequential samples from CHD patients followed up for a mean of 11.5 years. In total, 121,116 sequences were analyzed. The HDV evolution rate ranged from 9.5x10-3 to 1.2x10-3 substitutions/site/year and showed a negative correlation with the time elapsed between samples (p<0.05). An accumulation of transition-type changes was found to be responsible for higher evolution rates. The percentages of unedited and edited genomes and the quasispecies complexity showed no relationships with the evolution rate, but the fluctuations in the percentages of genomes and in complexity suggest continuous adaptation of HDV to the host conditions.
    Full-text · Article · Jun 2016
    • "In the analyzed group of HCV/HIV coinfected patients, viral quasispecies stability during treatment favored viral persistence, whereas decrease in the number of variants and/or emergence of new variants was associated with SVR. These results are in agreement with those reported for HVR1 by Sherman in HCV/HIV coinfected patients [16], as well as with Farci's studies on HVR1 in HCV monoinfected patients [25]. Furthermore, our current observations are also compatible with our previous work on 5'UTR in HCV-positive/HIV-negative patients [17] . "
    [Show abstract] [Hide abstract] ABSTRACT: Association between hepatitis C virus (HCV) quasispecies and treatment outcome among patients with chronic hepatitis C has been the subject of many studies. However, these studies focused mainly on viral variable regions (E1 and E2) and usually did not include human immunodeficiency virus (HIV)-positive patients. The aim of the present study was to analyze heterogeneity of the 5′untranslated region (5′UTR) in HCV/HIV coinfected patients treated with interferon and ribavirin. The HCV 5′UTR was amplified from serum and peripheral blood mononuclear cells (PBMC) samples in 37 HCV/HIV coinfected patients treated for chronic hepatitis C. Samples were collected right before treatment, and at 2, 4, 6, 8, 12, 20, 24, 36, 44, 48, 60, and 72 weeks. Heterogeneity of the 5′UTR was analyzed by single strand conformational polymorphism (SSCP), cloning and sequencing. Sustained virological response (SVR) was achieved in 46% of analyzed HCV/HIV co-infected patients. Stable SSCP band pattern was observed in 22 patients (62.9%) and SVR rate among these patients was 23%. Decline in the number of bands and/or shift in band positions were found in 6 patients (17.1%), 5 (83%) of whom achieved SVR (p=0.009). A novel viral genotype was identified in all but one of these patients. In 5 of these 6 patients a new genotype was dominant. 5′UTR heterogeneity may correlate with interferon and ribavirin treatment outcome. In the analyzed group of HCV/HIV coinfected patients, viral quasispecies stability during treatment favored viral persistence, whereas decrease in the number of variants and/or emergence of new variants was associated with SVR. Among injection drug users (IDU) patients, a new genotype may become dominant during treatment, probably due to the presence of mixed infections with various strains, which have different susceptibility to treatment.
    Full-text · Article · May 2015
    • "The best predictors of treatment outcome are virologic response kinetics, including rapid viral response (RVR), defined as HCV viral load below the level of detectability 4 weeks after treatment initiation, early viral response (EVR), defined as undetectable HCV load or a 2 log drop from baseline 12 weeks after therapy initiation, and SVR, defined as undetectable HCV load 24 weeks after therapy completion [81]. While undetectable HCV RNA at week 4 is the best predictor of SVR in co-infected patients, baseline serum HCV RNA is an independent predictor of SVR in HCV genotype 1 patients [82]. "
    [Show abstract] [Hide abstract] ABSTRACT: World-wide, hepatitis C virus (HCV) accounts for approximately 130 million chronic infections, with an overall 3% prevalence. Four to 5 million persons are co-infected with HIV. It is well established that HIV has a negative impact on the natural history of HCV, including a higher rate of viral persistence, increased viral load, and more rapid progression to fibrosis, end-stage liver disease, and death. Whether HCV has a negative impact on HIV disease progression continues to be debated. However, following the introduction of effective combination antiretroviral therapy, the survival of coinfected individuals has significantly improved and HCV-associated diseases have emerged as the most important co-morbidities. In this review, we summarize the newest studies regarding the pathogenesis of HIV/HCV coinfection, including effects of coinfection on HIV disease progression, HCV-associated liver disease, the immune system, kidney and cardiovascular disease, and neurologic status; and effectiveness of current anti-HIV and HCV therapies and proposed new treatment strategies.
    Full-text · Article · Mar 2011
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