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1.  Modulation of HCV Replication After Combination Antiretroviral Therapy in HCV/HIV Coinfected Patients 
Science translational medicine  2014;6(246):246ra98.
The hepatitis C virus (HCV) is an important contributor to morbidity and mortality in patients coinfected with human immunodeficiency virus (HIV). Coinfection results in increased HCV replication and more rapid rates of liver disease progression. The effect of HIV combination antiretroviral therapy (cART) on HCV replication has not been studied in depth. To address this issue, we enrolled a small cohort of HCV/HIV coinfected patients into a cART initiation trial, and used dynamic modeling combined with evaluation of immune responses and microarray profiles to determine how effective treatment of HIV affects HCV. Treatment with cART resulted in HCV flare and alanine aminotransferase (ALT) increase (2× or more increase from baseline) in a subset of treated patients. Subjects with evidence of hepatic injury (increased ALT) were more likely to have HCV-specific immune responses directed against HCV epitopes. Over time, HCV viral loads declined. Reproducible and biologically important gene expression changes occurred in patients who underwent successful cART, particularly with respect to downregulation of genes with known antiviral roles. Our findings suggest that the effective suppression of HIV by cART initiates a cascade of early and late events in treated patients with HCV. Early events involving downregulation of interferon-stimulated genes may lead to transiently increased viral replication and hepatic injury. At later time points, HCV viral load declines to levels comparable to those seen in the setting of HCV monoinfection. These findings support early antiretroviral therapy in those with HCV/HIV coinfection.
doi:10.1126/scitranslmed.3008195
PMCID: PMC4326686  PMID: 25101888
2.  Viral Kinetics in Hepatitis C or Hepatitis C/Human Immunodeficiency Virus–Infected Patients 
Gastroenterology  2005;128(2):313-327.
Background & Aims
Kinetic modeling of hepatitis C virus (HCV) response to interferon (IFN)-based therapy provides insights into factors associated with treatment outcomes. HCV/human immunodeficiency virus (HIV)–co-infected patients show lower response rates vs. HCV-monoinfected patients. Reasons for this remain unclear. This study evaluated kinetic parameters and treatment responses in co-infected vs monoinfected patients.
Methods
Co-infected patients were randomized within a US multicenter trial (ACTG 5071) to receive pegylatedinterferon (PEG-IFN) alfa-2a + ribavirin vs. IFN alfa-2a + ribavirin. Monoinfected controls were matched prospectively for treatment, genotype, age, sex, race, and histology. Quantitative HCV-RNA testing was performed at hours 0, 6, 12, 24, 48, and 72; days 7, 10, 14, 28, and 56; and weeks 12, 24, 48, and 72.
Results
Twelve HCV/HIV–co-infected and 15 HCV-monoinfected patients underwent viral kinetic sampling. Among HIV-positive patients the mean CD4+ count was 325 cells/mm3. Seventy-five percent of patients were genotype 1. The HCV-RNA level was undetectable at 72 weeks in 25% and 40% of co-infected and monoinfected patients, respectively. Phase 1/2 declines, free virus clearance rate, and infected hepatocyte death rate were not affected by co-infection status but differed by treatment. Efficiency (∈) ≥ 90% at 60 hours was associated with viral clearance (P = .02). Modeling with pooled parameters suggests baseline viral load is a key factor in time to response in this cohort. Predicted clearance time increased by 28% in co-infected patients.
Conclusions
Co-infection status did not affect key kinetic parameters. Among kinetic parameters, efficiency was associated significantly with viral clearance. Co-infected patients may require longer treatment duration than monoinfected patients given their generally higher baseline viral loads.
PMCID: PMC4036101  PMID: 15685543
3.  Mutations Associated with Occult Hepatitis B Virus Infection Result in Decreased Surface Antigen Expression In Vitro 
Journal of viral hepatitis  2012;19(10):716-723.
Occult hepatitis B virus infection is characterized by the absence of detectable hepatitis B surface antigen (HBsAg) in the serum, despite detectable HBV DNA. Investigations of the mechanisms underlying the development of occult HBV infection are lacking in the current literature, although viral mutations in the surface region, resulting in decreased HBsAg expression or secretion, represent one potential mechanism. Wild-type HBsAg expression vectors were constructed from genotype-matched chronic HBV sequences. Site-directed mutagenesis was then utilized to introduce three genotype A mutations – M103I, K122R, and G145A – associated with occult HBV infection in vivo, alone and in combination, into the wild-type HBsAg vectors. Transfection of Huh7 and HepG2 cell lines was performed, and cell culture supernatants and cell lysates were collected over 7 days to assess the effects of these mutations on extracellular and intracellular HBsAg levels. The G145A mutation resulted in significantly decreased extracellular and intracellular HBsAg expression in vitro. The most pronounced reduction in HBsAg expression was observed when all 3 mutations were present. The mutations evaluated in vitro in the current study resulted in decreased HBsAg expression and potentially increased hepatic retention and/or decreased hepatic secretion of synthesized HBsAg, which could explain the lack of HBsAg detection that is characteristic of occult HBV infection in vivo.
doi:10.1111/j.1365-2893.2012.01595.x
PMCID: PMC3442934  PMID: 22967103
G145A; HBV/HIV co-infection; HBsAg mutants; hepatitis B surface antigen (HBsAg); occult hepatitis B virus
4.  HIV Variability in the Liver and Evidence of Possible Compartmentalization 
AIDS Research and Human Retroviruses  2011;27(10):1117-1126.
Abstract
There is growing evidence to suggest that HIV may interact with several hepatic cell types; however, evaluation of HIV variability in liver tissue has not been addressed to date. Among 16 HIV-positive individuals examined, nine (56%) had detectable HIV RNA in the liver. The mean CD4 cell count for these nine individuals was 337 cells/mm3 (range: 0–601), while their mean plasma HIV RNA level was 106,974 copies/ml (range: 1200–320,740). Among individuals in this study with detectable HIV in both the plasma and the liver, the consensus gag nucleotide sequences for each tissue type were different for seven of seven (100%) individuals, while amino acid sequences were distinct for five of seven (71%). Consensus envelope (env) nucleotide and amino acid sequences were also distinct in the plasma and liver tissue for six of six (100%) individuals. Statistical evidence of compartmentalization between HIV in the plasma and in the liver was demonstrated, and multiple liver-specific amino acids were identified that may distinguish HIV variants replicating within the liver. These preliminary data demonstrate that HIV is frequently detectable in the liver of HIV-positive persons at various levels of immunosuppression. Possible compartmentalization may reflect tissue-specific selection pressures that drive viral adaptation to the liver microenvironment and may facilitate interactions with other hepatotropic viruses.
doi:10.1089/aid.2010.0329
PMCID: PMC3186706  PMID: 21417757
5.  HCV QUASISPECIES COMPLEXITY AND SELECTION IN HCV/HIV COINFECTED SUBJECTS TREATED WITH INTERFERON-BASED REGIMENS 
The Journal of infectious diseases  2010;201(5):712-719.
HCV/HIV coinfection 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 subjects. A subset of patients enrolled in ACTG 5071 underwent sampling to evaluate viral kinetics and HCV complexity changes. Early kinetic parameters, baseline complexity, and treatment outcomes, including rapid (RVR), early (EVR), and sustained (SVR) viral response were evaluated. HCV monoinfected subjects were matched to HCV/HIV coinfected subjects.
RESULTS
Baseline complexity was determined in 108 HCV/HIV coinfected subjects and 13 HCV controls. Quasispecies complexity was 2.24 in HCV/HIV and 1.90 in monoinfected subjects (p=0.14). Lower baseline complexity was associated with EVR (p=0.04) and approached significance for SVR. In patients who underwent viral kinetic modeling, complexity decrease was associated with RVR (p= 0.03), and was independent of the correlation between first phase viral decline efficiency and RVR.
CONCLUSION
Baseline HCV complexity is an independent predictor of early viral response in HCV/HIV subjects. Complexity decrease occurs by 4 weeks of interferon-based therapy and is associated with RVR. These findings may enhance predictive modeling of treatment outcomes in HCV/HIV patients.
doi:10.1086/650490
PMCID: PMC2827649  PMID: 20105080
HCV; HIV; RNA; Quasispecies; Complexity; Pegylated-interferon; Coinfection
6.  Genotypic characterization of symptomatic hepatitis E virus (HEV) infections in Egypt 
Background
Hepatitis E virus (HEV) is a common cause of acute viral hepatitis (AVH) in many developing countries. In Egypt, HEV seroprevalence is among the highest in the world; however, only a very limited number of Egyptian HEV sequences are currently available.
Objectives
The objectives were to determine the HEV genotype(s) currently circulating in Egypt.
Study Design
AVH patients without serologic evidence of hepatitis A, B, and C viruses were evaluated for possible HEV infection using serologic assays for anti-HEV IgM and anti-HEV IgG and real-time PCR for HEV RNA. Stool suspensions from suspected cases were inoculated into rhesus macaques to confirm the presence of HEV. Sequence analysis was utilized to determine HEV genotype.
Results
Of 287 subjects with AVH enrolled, 58 had serologic evidence of acute HEV infection. Stool samples for two of these patients were repeatedly positive for HEV RNA by real-time PCR. Macaques experimentally inoculated with these human stools also developed viremia. Sequence analysis of open reading frame (ORF) 1 demonstrated that these isolates belonged to HEV genotype 1 and were 3.9% – 9.5% divergent from other genotype 1 isolates. ORF2 was 5.3% – 8.7% divergent from previously reported Egyptian isolates.
Conclusions
This study strongly suggests that genotype 1 HEV related to other North African isolates is circulating in acute symptomatic patients in Egypt. Further evaluation of genotypic variability is underway in this highly endemic cohort and is considered an important component of our increased understanding of HEV pathogenesis.
doi:10.1016/j.jcv.2009.07.007
PMCID: PMC2753377  PMID: 19651539
Hepatitis E virus (HEV); Egypt; symptomatic; genotype; diversity
7.  Hepatitis E Virus Antibodies in Patients with Chronic Liver Disease 
Emerging Infectious Diseases  2009;15(3):479-481.
In the United States, the seroprevalence rate for hepatitis E virus (HEV) is ≈20%. This study examined HEV seroprevalence in persons with and without chronic liver disease. Our data indicate that HEV seropositivity is high in patients with chronic liver disease and that HEV seroprevalence increases significantly with age.
doi:10.3201/eid1503.080740
PMCID: PMC2681113  PMID: 19239770
Hepatitis E; chronic liver disease; seroprevalence; dispatch

Results 1-7 (7)