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Journal of viral hepatitis  2014;21(8):e74-e77.
Hepatitis E virus (HEV) has been reported to cause acute and chronic hepatitis in those with HIV infection and among solid organ transplant recipients in Europe. Limited data indicate that HEV is endemic in the United States, but the prevalence and significance of HEV infection among those with HIV and awaiting solid organ transplantation is unknown. We evaluated anti-HEV IgM and IgG antibodies and HEV RNA in 166 HIV-infected solid organ transplant candidates enrolled in the NIH HIV-Transplant Cohort. Overall prevalence of anti-HEV IgG approached 20% in both liver and renal transplant candidates. Evidence of recent infection was present in approximately 2% of liver transplant candidates and none of the kidney transplant candidates. HEV RNA was not detected in any patient. We conclude that markers of HEV infection are frequent among candidates for transplantation but active, ongoing viremia is not seen. Evidence of recent infection (acute on chronic) liver disease was present in liver but not kidney recipients.
PMCID: PMC4082745  PMID: 24773782
HEV; Transplant; Recipient; Renal; Liver
2.  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.
PMCID: PMC4326686  PMID: 25101888
3.  Human Immunodeficiency Virus and Liver Disease Forum 2012 
Hepatology (Baltimore, Md.)  2013;59(1):10.1002/hep.26638.
In the U.S. more than 1.1 million individuals are infected with the human immunodeficiency virus (HIV). These patients exhibit a high frequency of coinfections with other hepatotropic viruses and ongoing fibrosis leading to cirrhosis and liver-related mortality. The etiologies of liver disease include viral hepatitis coinfections, drug-related hepatotoxicity, fatty liver disease, and direct and indirect effects from HIV infection including increased bacterial translocation, immune activation, and presence of soluble proteins that modulate the hepatic cytokine environment. New treatments for HCV using direct acting agents appear viable, though issues related to intrinsic toxicities and drug:drug interactions remain. Recent research suggests that acute HCV infection, unrecognized hepatitis D infection, and hepatitis E may all represent emergent areas of concern. Antiretroviral agents, including those used in past years may represent risk factors for hepatic injury and portal hypertension. Key issues in the future include systematic implementation of liver disease management and new treatment in HIV-infected populations with concomitant injection drug use, alcohol use, and low socioeconomic status.
PMCID: PMC3849330  PMID: 23904401
HIV; HCV; HBV; HCC; Injury; Pathogenesis; Treatment; Epidemiology
4.  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.
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.
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.
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
Journal of viral hepatitis  2012;19(11):792-800.
Though health-related quality of life (HRQOL) is diminished in HCV/HIV, the relationship between virologic response or maintenance therapy with HRQOL in this population is unknown. ACTG 5178 was a phase 2, randomized trial, with 3 steps: Step 1: all subjects received PEG-IFN/ribavirin (P/R) for 12 weeks. Step 2: subjects who failed to achieve early viral response (EVR) were randomized to PEG-IFN or observational control for an additional 72 weeks. Step 3: subjects with EVR from Step 1 continued on P/R for a total of 72 weeks with 24 weeks follow-up off therapy. HRQOL, symptom distress and depression levels were measured at multiple time points. In Step 1 (n=329), there was a significant decline in HRQOL in all dimensions. In Step 3 (n=169), the overall HRQOL and 3 of its 8 dimensions (general health, role function and pain score) were increased, and achievement of SVR was associated with increased general health and cognitive function. In the Step 2 group (n=85), there was no significant change in HRQOL and no significant difference between groups (PEG-IFN vs. observational control). There was a significant decline in HRQOL during the initial 12 weeks of therapy. Thereafter the HRQOL profile differed for subjects with EVR vs. without EVR. Maintenance therapy with PEG-IFN had no impact on the HRQOL.
PMCID: PMC3468910  PMID: 23043386
HCV; HIV; confection; treatment; health related quality of life
6.  Therapeutic Approach to the Treatment-Naive Patient With Hepatitis C Virus Genotype 1 Infection: A Step-by-Step Approach 
The treatment of hepatitis C virus infection has rapidly evolved after the approval and use of new protease inhibitor antiviral agents. This change affects the evaluation process, monitoring, and adverse event management. Treatments have become both more complex and more efficacious.
Recent advances in the treatment of hepatitis C virus infection (HCV) have led to high rates of viral cure. However, the use of newly approved protease inhibitors with activity against HCV still requires careful patient selection, counseling, and decision making before initiation of treatment. Laboratory work-up, staging of liver disease, and careful review of comorbid conditions is mandatory. Patients with cirrhosis may require treatment regimens that differ from those without cirrhosis. Because pegylated interferon alfa and ribavirin remain a key part of the treatment regimen, absolute and relative contraindications to their use must be considered. Management of common adverse events including anemia and rash must be embraced by the healthcare provider.
PMCID: PMC3529612  PMID: 22843782
7.  Human Immunodeficiency Virus and Liver Disease Forum 2010: Conference Proceedings 
Hepatology (Baltimore, Md.)  2011;54(6):2245-2253.
Liver disease continues to represent a critical mediator of morbidity and mortality in those with human immunodeficiency virus (HIV) infection. The frequent presence and overlap of concomitant injurious processes, including hepatitis C virus and hepatitis B virus infections, hepatoxicity associated with antiretroviral therapeutic agents, alcohol, and other toxins, in the setting of immunosuppression lead to rapid fibrotic progression and early development of end-stage liver disease. This conference summary describes the proceedings of a state-of-the-art gathering of international experts designed to highlight the status of current research in epidemiology, natural history, pathogenesis, and treatment of HIV and liver disease.
PMCID: PMC3795389  PMID: 21898501
8.  Direct Acting Antiviral Agents and the Path to Interferon Independence 
Chronic infection with hepatitis C virus (HCV) is a major global health problem—there are approximately 120–130 million chronic infections worldwide. Since discovery of HCV 24 y ago, there has been a relentless effort to develop successful antiviral therapies. Studies of interferon- □(IFN)-based therapies have helped define treatment parameters, and these treatment strategies have cured a substantial percentage of patients. However, IFN must be injected, and there are problems with tolerability, adherence, and incomplete response in a large percentage of patients. New drug candidates designed to target the virus or the host have recently been introduced at an unprecedented pace. In phase I–III studies, these agents have exceeded expectations and achieved rates of response previously not thought possible. We are therefore entering a new era of therapy for HCV infection and interferon independence.
PMCID: PMC4049632  PMID: 23872239
DAA; NS3/4A protease inhibitor; nucleoside/nucleotide; non-nucleoside
9.  Liver Transplant Outcomes in HIV(+) Hemophilic Men 
Hepatitis C virus infection is the major cause of end-stage liver disease and the major indication for transplantation (OLTX), including among HIV-HCV co-infected individuals. The age of HCV acquisition differs between hemophilic and non-hemophilic candidates, which may affect liver disease outcomes.
The purpose of the study was to compare rates of pre- and post-OLTX mortality between co-infected hemophilic and non-hemophilic subjects without hepatocellular cancer participating in the Solid Organ Transplantation in HIV Study (HIV-TR).
Clinical variables included age, gender, race, liver disease etiology, BMI, antiretroviral therapy, MELD score, CD4+ cell count, HIV RNA PCR, and HCV RNA PCR. Time to transplant, rejection, and death were determined.
Of 104 HIV-HCV positive subjects enrolled, 34 (32.7%) underwent liver transplantation, including 7 of 15 (46.7%) hemophilic and 27 of 89 (30.3%) non-hemophilic candidates. Although hemophilic subjects were younger, median 41 vs. 47 years, p=0.01, they were more likely than non-hemophilic subjects to die pre-OLTX, 5 (33.3%) vs. 13 (14.6%), p=0.03, and reached MELD=25 marginally faster, 0.01 vs. 0.7 years, p=0.06. The groups did not differ in baseline BMI, CD4, detectable HIV RNA, detectable HCV RNA, time to post-OLTX death (p=0.64), graft loss (p=0.80), or treated rejection (p=0.77). The rate of rejection was 14% vs. 36% at 1-year and 36% vs. 43% at 3-year, hemophilic vs. non-hemophilic subjects, respectively, and post-OLTX survival, 71% vs. 66% at 1-year and 38% vs. 53% at 3-year.
Despite similar transplant outcomes, pre-transplant mortality is higher among co-infected hemophilic than non-hemophilic candidates.
PMCID: PMC4351753  PMID: 22762561
hemophilia; hepatitis C liver disease; HIV-HCV co-infection; liver transplantation
10.  Sustained Long-term Antiviral Maintenance Therapy in HCV/HIV Coinfected Patients (SLAM-C) 
HCV/HIV coinfection treatment is suboptimal with low SVR rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated-interferon maintenance therapy was performed by the NIH-funded ACTG network.
HCV treatment naïve and non-responding interferon-experienced subjects with confirmed HCV and HIV, CD4>200 cells/mm3, and at least Stage 1 fibrosis were enrolled, and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg/week (PEG) + weight-based ribavirin to determine response status. Non-responder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist.
330 subjects were enrolled; median age was 48 years; 43% White, 37% Black, non-Hispanic; 83% male; CD4+ 498 cells/mm3; 32% were interferon experienced; 74% had entry HIV RNA<50 cp/ml. EVR was observed in 55.9% and 42.5% achieved cEVR. A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm.
Lack of fibrotic progression in the control arm was unexpected, and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression and use of antiretroviral regimens that may be less toxic than prior generations of therapy.
PMCID: PMC3017670  PMID: 20921898
HCV; HIV; Maintenance; Racial Disparity; Fibrosis
11.  Occult Hepatitis B–Clinical Implications and Treatment Decisions 
Digestive diseases and sciences  2010;55(12):3328-3335.
First reported in 1978, occult hepatitis B is a term used to describe the presence of hepatitis B virus (HBV) DNA without hepatitis B surface antigenemia. The prevalence of occult HBV is unclear and depends in part on the sensitivity of the hepatitis B surface antigen (HBsAg) and DNA assays used as well as the prevalence of HBV infection in the study population. The origin of occult HBV also remains in question. Several mechanisms have been hypothesized including mutations in the regulatory regions of the HBV genome, persistence of Ig-bound HBV immune complexes, viral interference, and blockage of free HBsAg secretion. Occult HBV has important clinical implications such as transmission through blood transfusion, reactivation in the setting of immunosuppression, and interference with hepatitis C treatment. To date, there is little date pertaining to the treatment of occult HBV outside of the setting of chemotherapy-induced HBV reactivation.
PMCID: PMC3001399  PMID: 20927592
occult HBV; chronic hepatitis B; HBV DNA; HBs antigenemia
12.  Epigenetic modification of FOXP3 in patients with chronic HIV infection 
Human immunodeficiency virus type 1 (HIV-1) modulates host cell epigenetic machinery to control its own replication and induce immune suppression. HIV-1 infection leads to activation of T regulatory cell (Treg), but the mechanism underlying this immune modulation is unclear. Treg plays a prominent role in gut-mucosal immune tolerance by restraining excessive effector T-cell responses, a mechanism that is known to be disturbed in chronic HIV-1 infection. DNA methylation plays a major role in Treg lineage commitment and immune homeostasis, which may be regulated by HIV. To investigate the mechanisms of aberrant methylation of the Treg marker FOXP3 in HIV-1 infection, we evaluated the expression pattern of methylation related enzymes and its correlation to FOXP3 methylation.
FOXP3 promoter methylation in the colon mucosa and peripheral blood from HIV-infected patients and control subjects was measured using Pyrosequencing. Gene expression pattern of DNA methylation enzymes in the colon mucosa was investigated by Microarray and quantitative rt-PCR analysis in the same subjects.
FOXP3 promoter was significantly (p=< 0.0001) demethylated in HIV-infected patients compared to control subjects in both tissues. Expression of DNA methyltransferase 1 (DNAMT1), DNA methyltransferase 1-associated protein 1(DMAP1), methyltransferase like 7B (METTL7B), and methyltransferase like 10 (METTL10), were significantly down regulated in HIV-infected patients compared to controls and had a significant positive correlation to FOXP3 promoter methylation.
We present evidence suggesting that altered methylation pattern of FOXP3 and accordingly higher Treg frequency in gut mucosa of HIV infected patients may be due to aberrant methylation processing in HIV.
PMCID: PMC3871978  PMID: 23846566
HIV; FOXP3; Methylation; Epigenetics; Methylation enzymes
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.
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.
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.
PMCID: PMC2827649  PMID: 20105080
HCV; HIV; RNA; Quasispecies; Complexity; Pegylated-interferon; Coinfection
14.  Use of a Standardized Patient Exercise to Assess Core Competencies During Fellowship Training 
The Accreditation Council for Graduate Medical Education requires fellows in many specialties to demonstrate attainment of 6 core competencies, yet relatively few validated assessment tools currently exist. We present our initial experience with the design and implementation of a standardized patient (SP) exercise during gastroenterology fellowship that facilitates appraisal of all core clinical competencies.
Fellows evaluated an SP trained to portray an individual referred for evaluation of abnormal liver tests. The encounters were independently graded by the SP and a faculty preceptor for patient care, professionalism, and interpersonal and communication skills using quantitative checklist tools. Trainees' consultation notes were scored using predefined key elements (medical knowledge) and subjected to a coding audit (systems-based practice). Practice-based learning and improvement was addressed via verbal feedback from the SP and self-assessment of the videotaped encounter.
Six trainees completed the exercise. Second-year fellows received significantly higher scores in medical knowledge (55.0 ± 4.2 [standard deviation], P  =  .05) and patient care skills (19.5 ± 0.7, P  =  .04) by a faculty evaluator as compared with first-year trainees (46.2 ± 2.3 and 14.7 ± 1.5, respectively). Scores correlated by Spearman rank (0.82, P  =  .03) with the results of the Gastroenterology Training Examination. Ratings of the fellows by the SP did not differ by level of training, nor did they correlate with faculty scores. Fellows viewed the exercise favorably, with most indicating they would alter their practice based on the experience.
An SP exercise is an efficient and effective tool for assessing core clinical competencies during fellowship training.
PMCID: PMC2931209  PMID: 21975896
15.  HIV and Liver Disease Forum 2008: Conference Proceedings 
Hepatology (Baltimore, Md.)  2007;45(6):1566-1577.
PMCID: PMC2786959  PMID: 17538932
HIV; HCV; HBV; coinfection; pathogenesis; liver injury
16.  Randomized Controlled Study of Tenofovir and Adefovir in Chronic Hepatitis B Virus and HIV Infection: ACTG A5127 
Hepatology (Baltimore, Md.)  2006;44(5):1110-1116.
Chronic hepatitis B virus (HBV) infection is an important cause of morbidity and mortality in subjects coinfected with HIV. Tenofovir disoproxil fumarate (TDF) and adefovir dipivoxil (ADV) are licensed for the treatment of HIV-1 and HBV infection, respectively, but both have in vivo and in vitro activity against HBV. This study evaluated the anti-HBV activity of TDF compared to ADV in HIV/HBV-coinfected subjects. ACTG A5127 was a prospective randomized, double-blind, placebo-controlled trial of daily 10 mg of ADV versus 300 mg of TDF in subjects with HBV and HIV coinfection on stable ART, with serum HBV DNA ≥ 100,000 copies/mL, and plasma HIV-1 RNA ≤ 10,000 copies/mL. This study closed early based on results of a prespecified interim review, as the primary noninferiority end point had been met without safety issues. Fifty-two subjects were randomized. At baseline, 73% of subjects had a plasma HIV-1 RNA < 50 copies/mL, 86% were HBeAg positive, 94% were 3TC resistant, median serum ALT was 52IU/L, and 98% had compensated liver disease. The mean time-weighted average change in serum HBV DNA from baseline to week 48 (DAVG48) was −4.44 log10 copies/mL for TDF and −3.21 log10 copies/mL for ADV. There was no difference in toxicity between the 2 treatment arms, with 11 subjects (5 ADV and 6 TDF) experiencing elevations of serum ALT on treatment. In conclusion, over 48 weeks, treatment with either ADV or TDF resulted in clinically important suppression of serum HBV DNA. Both drugs are safe and efficacious for patients coinfected with HBV and HIV.
PMCID: PMC4114764  PMID: 17058225
17.  Peginterferon Alfa-2a plus Ribavirin versus Interferon Alfa-2a plus Ribavirin for Chronic Hepatitis C in HIV-Coinfected Persons 
The New England journal of medicine  2004;351(5):451-459.
Chronic hepatitis C virus (HCV) infection is a cause of major complications in persons who are also infected with the human immunodeficiency virus (HIV). However, the treatment of HCV infection in such persons has been associated with a high rate of intolerance and a low rate of response. We conducted a multicenter, randomized trial comparing peginterferon plus ribavirin with interferon plus ribavirin for the treatment of chronic hepatitis C in persons coinfected with HIV.
A total of 66 subjects were randomly assigned to receive 180 μg of peginterferon alfa-2a weekly for 48 weeks, and 67 subjects were assigned to receive 6 million IU of interferon alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks. Both groups received ribavirin according to a dose-escalation schedule. At week 24, subjects who did not have a virologic response (those who had an HCV RNA level greater than or equal to 60 IU per milliliter) underwent liver biopsy, and medications were continued in subjects with either a virologic response or histologic improvement.
Treatment with peginterferon and ribavirin was associated with a significantly higher rate of sustained virologic response (an HCV RNA level of less than 60 IU per milliliter 24 weeks after completion of therapy) than was treatment with interferon and ribavirin (27 percent vs. 12 percent, P=0.03). In the group given peginterferon and ribavirin, only 14 percent of subjects with HCV genotype 1 infection had a sustained virologic response (7 of 51), as compared with 73 percent of subjects with an HCV genotype other than 1 (11 of 15, P<0.001). Histologic responses were observed in 35 percent of subjects with no virologic response who underwent liver biopsy.
In persons infected with HIV, the combination of peginterferon and ribavirin is superior to the combination of interferon and ribavirin in the treatment of chronic hepatitis C. These regimens may provide clinical benefit even in the absence of virologic clearance. The marked discrepancy in the rates of sustained virologic response between HCV genotypes indicates that strategies are needed to improve the outcome in persons infected with HCV genotype 1.
PMCID: PMC4113392  PMID: 15282352
18.  Effects of HCV Treatment on Cytokine Expression During HCV/HIV Coinfection 
There is growing evidence that cytokine expression is linked to hepatitis C virus (HCV) pathogenesis and treatment response rates among HCV-monoinfected persons. However, because of the profound effects of human immunodeficiency virus (HIV) coinfection on HCV, it is not clear if these observations are also true for HCV/HIV-coinfected individuals. Serum expression of the proinflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) and the fibrogenic cytokine transforming growth factor-β1 (TGF-β1) were measured in HCV/HIV-coinfected persons at baseline and at week 24 of HCV therapy. Higher levels of IL-8 and TGF-β were demonstrated among nonwhite subjects at baseline. Increases in TNF-α and IL-8 expression were found at week 24 of HCV therapy, suggesting that enhanced proinflammatory cytokine production may occur during HCV treatment. However, cytokine levels were not predictive of HCV virologic, biochemical, or histologic response. Although previous studies conducted among HCV-monoinfected individuals have suggested that cytokine levels could predict the virologic response to therapy, no such associations were observed among HCV/HIV-coinfected persons, suggesting that they may respond differently to treatment than do their HCV-monoinfected counterparts.
PMCID: PMC4113398  PMID: 17115902
20.  Viral Factors Associated with Cytokine Expression During HCV/HIV Co-Infection 
Co-infection with human immunodeficiency virus (HIV) is associated with reduced hepatitis C virus (HCV) treatment response and accelerated HCV disease. Cytokines, as mediators of immune responses, inflammation, and fibrogenesis, may underlie important differences in HCV pathogenesis during HIV co-infection. We previously found that serum interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) increased after HCV therapy with interferon (IFN) in HCV/HIV co-infected patients; however, cytokine levels were not predictive of HCV therapeutic response. Here, we examined viral factors associated with expression of IL-8, TNF-α, and transforming growth factor-β1 (TGF-β1) in uninfected, HCV mono-infected, HIV mono-infected, and HCV/HIV co-infected persons. HIV co-infection was associated with decreased IL-8 detection but not TNF-α detection. A significant interaction effect demonstrated that HIV infection was associated with elevated TGF-β1 in HCV-positive individuals but not in HCV-negative individuals. The induction of a sustained profibrotic signal, such as TGF-β1, by HIV may cause accelerated liver fibrosis during HCV/HIV co-infection and may hinder the host’s ability to mount an effective HCV-specific immune response. Further studies are warranted to identify noninvasive markers of liver disease for the clinical management of HCV disease, particularly when liver biopsies have not been performed or are contraindicated.
PMCID: PMC4066618  PMID: 17477814
21.  Relationships between cellular immune responses and treatment outcomes with interferon and ribavirin in HIV/hepatitis C virus co-infection 
AIDS (London, England)  2006;20(3):345-351.
To test the hypothesis that hepatitis C virus (HCV)-specific interferon (IFN)γ immune responses are correlated with HCV virological response following treatment in subjects with HIV-1 and HCV co-infection.
Immune responses were studied in a treatment trial comparing standard interferon alfa (IFN) to pegylated interferon alfa (PEG-IFN), each with ribavirin (R).
Using HCV antigens core, NS3 and NS5, and Candida, enzyme-linked immunosorbent spots on peripheral blood mononuclear cells measured IFNγ and interleukin (IL)-10 production. Immunologic, virologic and clinical variables were modeled using recursive partitioning (CART) to identify factors associated with HCV virological response at week 24 (VR) and week 72 (SVR) in 108 patients.
There were no significant differences in baseline IFNγ immune responses and higher IL-10 to NS3 in subjects with VR versus non-responders. Subjects who had significant decreases in IL-10 responses at week 24 compared to baseline for NS3, NS5, or summed HCV responses were more likely to be VR. Using baseline immunological responses and clinical data in CART models, patients who were randomized to PEG-IFN/Rand had high IL-10 responses to summed HCV proteins were more likely to be VR (73%), whereas those on IFN/R who had low IFNγ responses to Candida were less likely to be VR (5%). The main correlate of SVR for genotype-1 subjects was maintenance of HCV-specific IFNγ responses from baseline to week 72.
In this cohort of subjects with HIV and HCV, a decrease in HCV-specific IL-10 responses and maintenance of IFNγ responses during treatment with IFN were associated with week 24 or 72 virological response.
PMCID: PMC4060610  PMID: 16439867
hepatitis C virus; interferon α; cellular immunity; interferon gamma; interleukin 10
22.  Antigen-specific immune responses and liver histology in HIV and hepatitis C coinfection 
AIDS (London, England)  2005;19(8):767-773.
To test the hypothesis that antigen-specific interferon (IFN)γ responses are correlated with milder liver disease in subjects coinfected with HIV-1 and hepatitis C virus (HCV).
Cellular immune responses were studied in a cohort with HIV/HCV coinfection (n = 107) who underwent liver biopsy.
We measured HCV-specific and recall responses in peripheral blood mononuclear cells using IFNγ and interleukin (IL)-10 ELISpots, and correlated these immune responses with liver histology. The relationship of immunologic, virologic and clinical variables to inflammation and fibrosis was modeled using recursive partitioning.
There were significant negative correlations between inflammatory scores and IFNγ production in response to the HCV proteins core, NS5 and summed HCV responses. Lower fibrosis scores were also correlated with higher IFNγ production in response to NS5 and summed HCV proteins. Higher IFNγ production in response to Candida was significantly associated with lower inflammatory and fibrosis scores. In multivariable models, factors associated with severe fibrosis were lower IFNγ responses to Candida and summed HCV proteins. Factors associated with severe inflammation were detectable HIV viral load and lower HCV viral load, while predictors of mild inflammation included undetectable HIV viral load and higher IFNγ response to Candida.
In this cohort of subjects coinfected with HIV and HCV, antigen-specific IFNγ responses are correlated with milder inflammation and fibrosis. Immunological responses best predicted severity of fibrosis, while clinical variables and recall antigen responses best predicted severity of inflammation.
PMCID: PMC4050654  PMID: 15867490
Hepatitis C virus; liver histology; cellular immunity; interferon gamma; fibrosis; interleukin 10
23.  Immune activation in HIV/HCV-infected patients is associated with low-level expression of liver expressed antimicrobial peptide-2 (LEAP-2) 
Journal of clinical pathology  2013;66(11):967-975.
Immune activation is one of the main features of HIV/Hepatitis C virus (HCV) infections and has been linked to the disturbance of the gut-associated lymphoid tissue (GALT). In chronic HIV infection, loss of GALT integrity results in translocation of microbial products and chronic immune activation. We explored the relationship between bacterial translocation and specific colonic proteins, including liver expressed antimicrobial peptide (LEAP 2) which may play a role in modulating the bacterial translocation process.
A total of 40 subjects (10 HIV/HCV, 10 HIV, 10 HCV-infected patients and 10 controls) were enrolled and underwent serum and colonic tissue sampling. The levels of immune activation were evaluated by measuring plasma sCD27, and the levels of selected proinflammatory, Th2 and regulatory cytokines in both the plasma and supernatant of CD3-stimulated intraepithelial lymphocytes. We also evaluated LEAP-2 expression in the colon biopsies using Affymetrix Human Gene 1.0 ST (HuGene) and fluorescent immunohistochemistry.
Increased levels of sCD27 were observed in HIV/HCV coinfected (p=0.03) and HIV monoinfected (p=0.04) patients compared with controls consistent with the presence of immune activation. The chip array identified LEAP-2 expression as a key marker associated with immune activation. LEAP-2 expression in HIV, HCV and HIV/HCV-infected patients was significantly lower compared with controls, and was significantly negatively correlated (p=0.03, r=−0.44) with sCD27.
Our data suggests that HCV and HIV infections are associated with decreased expression of LEAP-2 in colonic tissue. This may represent a key mechanism for enhanced microbial translocation and immune activation in HIV/HCV-infected patients.
PMCID: PMC3987848  PMID: 23940131
24.  Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection 
The New England journal of medicine  2011;365(11):10.1056/NEJMoa1014463.
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.
We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon–ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48.
Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, −2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001).
In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon–ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE number, NCT00758043.)
PMCID: PMC3809077  PMID: 21916639
25.  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.
PMCID: PMC3442934  PMID: 22967103
G145A; HBV/HIV co-infection; HBsAg mutants; hepatitis B surface antigen (HBsAg); occult hepatitis B virus

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