Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon–ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, −10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations.
African Americans infected with hepatitis C virus (HCV) are less responsive than whites to interferon-based therapy. HCV quasi species have been implicated. Quasi-species complexity and diversity were evaluated in matched African American and white individuals. Complexity and diversity in the first hypervariable region were similar in the 2 groups. Both the frequency of nonsynonymous amino acid substitutions and the mean ratio of nonsynonymous mutations to synonymous mutations were greater in clones derived from white patients. Racial differences in amino acid usage at otherwise conserved positions were observed. Differences in amino acid representation at key positions are suggestive of immunologic and functional selection along racial lines.
Patients coinfected with the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) were studied with regard to nucleotide sequence variability in the E2/NS1 first hypervariable region of the HCV genome. The nucleotide variability within individual patients was compared to patients infected only with HCV. The proportion of predicted synonymous and nonsynonymous amino acid changes, and the relationship to putative high-antigenicity sites, were evaluated in the hypervariable envelope domain. Ninety-one clones from 10 patients with HCV/HIV coinfection were sequenced, following polymerase chain reaction (PCR) amplification of the hypervariable region. The control HCV group included 53 clones from 7 patients. Sequence analysis encompassed the region coding for amino acids 384 to 414. Consensus sequences from each patient were used as the internal standard for nonsynonymous amino acid codon variability. Cumulative proportional comparison at each amino acid site revealed increased variability in HCV RNA from patients with HCV/HIV coinfection versus HCV alone (P < .05). The greatest variability was observed at amino acids 386, 397, 400, 402, 405, 407, and 414, with > l0 percent clonal variation at these sites. Jameson-Wolf plots were used to predict putative high-antigenicity domains. Nonsynonymous clonal variation resulted in alteration of putative antigenic sites within the hypervariable region. All clones had at least one high-probability site. Clones with unique predicted antigenic domains were observed more frequently in HIV/HCV coinfected patients, and, independent of viral titer, were consistent with increased sequence variability. These data suggest an accumulation of envelope variants in the HCV/HIV coinfected patients, which could be related to ineffective viral clearance, and may help explain prior reports of interferon (IFN) resistance in this patient group.
Background: HIV infection disproportionally affects African Americans. Liver disease is a major cause of non-HIV morbidity and mortality in this population. Substance abuse accelerates HIV disease and may facilitate progression of liver disease. This study investigated the relationship between sex differences and cocaine use with liver injury, characterized as hepatic fibrosis. Materials and Methods: A cross-sectional study was conducted on 544 African Americans [369 people living with HIV (PLWH) and 175 HIV seronegative] from the Miami Adult Studies on HIV (MASH) cohort. Cocaine use was determined with a validated self-reported questionnaire and confirmed with urine screen. Fasting blood was used to estimate liver fibrosis using the noninvasive fibrosis-4 (FIB-4) index. Results: Men living with HIV had 1.79 times higher odds for liver fibrosis than women living with HIV (p = 0.038). African American women had higher CD4 count (p = 0.001) and lower HIV viral load (p = 0.011) compared to African American men. Fewer women (PLWH and HIV seronegative) smoked cigarettes (p = 0.002), and fewer had hazardous or harmful alcohol use (p < 0.001) than men. Women also had higher body mass index (kg/m2) (p < 0.001) compared to men. No significant association was noted among HIV seronegative participants for liver fibrosis by sex differences or cocaine use. Among African Americans living with HIV, cocaine users were 1.68 times more likely to have liver fibrosis than cocaine nonusers (p = 0.044). Conclusions: Sex differences and cocaine use appear to affect liver disease among African Americans living with HIV pointing to the importance of identifying at-risk individuals to improve outcomes of liver disease.
Background and aim The hepatitis C virus (HCV) is a single-strand RNA virus that infects millions of people worldwide. Recent advances in therapy have led to viral cure using two- and three- drug combinations of direct acting inhibitors of viral replication. CCR5 is a chemokine receptor that is expressed on hepatocytes and represents a key co-receptor for HIV. We evaluated the effect of CCR5 blockade or knockdown on HCV replication in Huh7.5JFH1 cells. Methods Cells were exposed to varying concentrations of maraviroc (CCR5 inhibitor), cenicriviroc (CCR2/CCR5 inhibitor), sofosbuvir (nucleotide polymerase inhibitor), or raltegravir (HIV integrase inhibitor). Results HCV RNA was detected utilizing two qualitative strand-specific RT-PCR assays. HCV core antigen and NS3 protein was quantified in the supernatant and cell lysate, respectively. siRNA was utilized to knockdown CCR5 gene expression in hepatocytes. Alternatively, anti-CCR5 antibodies were employed to block the receptor. Supernatant levels of HCV RNA (expressed as fold change) were not reduced in the presence of raltegravir but were reduced 8.55-fold and 12.42-fold with cenicriviroc and maraviroc, respectively. Sofosbuvir resulted in a 16.20-fold change in HCV RNA levels. HCV core and NS3 protein production was also reduced in a dose-dependent manner. Two distinct anti-CCR5 antibodies also resulted in a significant reduction in HCV protein expression, as did siRNA knockdown of CCR5 gene expression. Conclusions These data provide evidence that CCR5 modulation could have a significant effect on HCV replication in an in vitro system. Further evaluation of the role of CCR5 inhibition in clinical settings may be warranted.
Limited data suggest that low T-helper cell levels may be observed in hepatitis C virus (HCV) monoinfected patients with decompensated liver disease. We sought to determine the distribution and relationship of T-helper cells (CD4) to liver fibrosis in HCV-monoinfected patients before and during pegylated interferon (PegIFN) therapy. CD4 populations were prospectively determined using flow cytometry. All subjects had compensated liver disease. Baseline and subsequent CD4 counts at treatment weeks 12, 24, 36 and 48 and at two time points following treatment discontinuation (weeks 60 and 72) were evaluated. Ishak score was determined by a central pathologist. At baseline, data from 267 subjects were available. Mean age was 50 and 68% were male/Caucasian. HCV viral load was >800 000 IU/mL in 55%. Nearly half (48%) were Ishak 4-6 with all stages represented. Mean CD4 count was 1004 cells/mm(3) + or - 400, and 6% had counts <500. There was a trend towards lower CD4 counts among cirrhotic subjects (P = 0.07). A CD4 decrease was noted following PegIFN initiation. Mean CD4 decline was 38.9% and was statistically significant for all fibrosis stages compared with baseline levels, but not between fibrosis levels. CD4 counts <500 cells/mm(3) are seen in <10% of HCV-monoinfected subjects. A trend towards lower CD4 counts in subjects with advanced fibrosis was observed. However, at baseline and during/after PegIFN therapy, no significant differences were observed between groups. CD4 counts declined during PegIFN treatment, but returned to baseline after completion. The significance of these findings in terms of disease progression and treatment response requires further evaluation.
Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) type 1 is common. Rates of liver-related morbidity and mortality have been increasing in the coinfected population, and treatment for HCV infection in this group remains a challenge. The HCV-monoinfected population, especially patients infected with HCV genotype 2 or 3, has benefited dramatically from the advent of treatment with pegylated interferon plus ribavirin; rates of sustained virological response approach 55%. Coinfected patients lag behind, with rates of sustained virological response ranging between 26% and 40%; rates of sustained virological response are even lower among patients infected with HCV genotype 1. It is encouraging, however, that therapies known to be safe for treating monoinfected patients have been proven to be generally safe and well tolerated in patients coinfected with HIV and HCV, as well. Future therapies, some of which are currently in development, will likely include new targets, such as helicase and polymerase. It is hoped that, as more-effective agents are discovered, the disparity in treatment response will diminish.
