Hepatitis C virus (HCV) quasispecies complexity and selection in HCV/HIV-coinfected subjects treated with interferon-based regimens.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Prevalence of mutations in hepatitis C virus core protein associated with alteration of NF-kappaB activation.

The hepatitis C virus (HCV) core protein is a key structural element of the virion but also affects a number of cellular pathways, including nuclear factor kappaB (NF-kappaB) signaling. NF-kappaB is a transcription factor that regulates both anti-apoptotic and pro-inflammatory genes and its activation may contribute to HCV-mediated pathogenesis. Amino acid sequence divergence in core is seen at the genotype level as well as within patient isolates. Recent work has implicated amino acids 9-11 of core in the modulation of NF-kappaB activation. We report that the sequence RKT is highly conserved (93%) at this position across all HCV genotypes, based on sequences collected in the Los Alamos HCV database. Of the 13 types of variants present in the database, the two most prevalent substitutions are RQT and RKP. We further show that core encoding RKP fails to activate NF-kappaB signaling in vitro while NF-kappaB activation by core encoding RQT does not differ from control RKT core. The effect of RKP core is specific to NF-kappaB signaling as activator protein 1 (AP-1) activity is not altered. Further studies are needed to assess potential associations between specific amino acid substitutions at positions 9-11 and liver disease progression and/or response to treatment in individual patients.

The prevalence and significance of occult hepatitis B virus in a prospective cohort of HIV-infected patients.

BACKGROUND: Occult hepatitis B virus (HBV) is defined as low-level HBV DNA without hepatitis B surface antigen (HBsAg). Prevalence estimates vary widely. We determined the prevalence of occult HBV at the University of Cincinnati Infectious Diseases Center (IDC). METHODS: Patients in the IDC HIV database (n = 3867) were randomly selected using a 25% sampling fraction. Samples were pooled for HBV nucleic acid extraction. Pools were tested for HBV DNA by a real-time polymerase chain reaction (PCR) assay to co-amplify core/surface protein regions. The PCR assay was run on all individual samples from each DNA pool. DNA samples were tested for HBV serologic markers. RESULTS: A total of 909 patients without known HBV were selected. The mean CD4 count was 384 cells/mm. Forty-three patients were HBV DNA. Twelve of 43 were DNA/HBsAg (95% confidence interval for database: 0.58% to 1.90%). Five of 12 were negative for all serologic markers. Alanine aminotransferase, aspartate aminotransferase, and HBV DNA titers were elevated in HBsAg patients versus occult patients and versus HIV-monoinfected patients. No other significant differences were detected. No occult HBV patient was on treatment with anti-HBV activity. CONCLUSIONS: Forty-three percent of those with HBV were not previously identified as HBV, indicating the need for ongoing screening in high-risk populations. Occult HBV may occur in persons with all negative serologic markers, representing a challenge for identification.

HCV kinetics, quasispecies, and clearance in treated HCV-infected and HCV/HIV-1-coinfected patients with hemophilia.

Hepatitis C virus (HCV) treatment response rates remain low in HCV/HIV-1-coinfected individuals compared with those with HCV alone. Persons with inherited coagulation disorders have high rates of HCV and HIV-1 infection, but HCV treatment trials in this patient population are scarce. We hypothesized that differences by infection status in HCV viral kinetics would be associated with differences in HCV quasispecies complexity over time and with treatment response disparities. Coinfected and monoinfected patients were enrolled in a treatment trial for pegylated-interferon alpha-2a (peg-IFN) + ribavirin. Patients were treated for 48 weeks and followed for an additional 24. Quantitative HCV RNA was tested at multiple times during and after treatment. Viral kinetic parameters associated with response were estimated with a mathematical model. Quasispecies emergence was determined via heteroduplex complexity assay. Twenty-two patients were HCV RNA-positive at baseline, with no significant demographic or virological differences by infection status. Five of eleven (45%) of monoinfected and 3 of 11 (27%) of coinfected patients achieved sustained viral response (SVR). Peg-IFN efficacy (epsilon) of 90% or greater was associated with probability of end-of-treatment response (ETR) (P = .001) and SVR (P = .06). Patients with SVR had lower baseline quasispecies complexity than those without SVR (P = .07). Those with epsilon of 90% or greater also had lower baseline complexity (P = .07). Coinfection status mediated changes in complexity over time (P = .04). In conclusion, low pretreatment quasispecies complexity may predict peg-IFN response; early peg-IFN response is critical for sustained HCV clearance and is altered in coinfection. Further studies are warranted.