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1.  Evaluation of Hepatitis C Virus as a Risk Factor for HIV-Associated Neuroretinal Disorder 
Hepatitis C virus (HCV) is a newly identified risk factor for HIV-associated neuroretinal disorder (HIV-NRD). Genetic analysis suggests that alterations in the anti-inflammatory IL-10 signaling pathway increase susceptibility to both HIV-NRD and HCV infection. Inflammation may provide a mechanistic link between HCV and HIV-NRD.
Background. Both hepatitis C virus (HCV) and human immunodeficiency virus (HIV) penetrate the central nervous system. HIV-associated neuroretinal disorder (HIV-NRD), a visual impairment of reduced contrast sensitivity and reading ability, is associated with cytokine dysregulation and genetic polymorphisms in the anti-inflammatory interleukin 10 (IL-10) signaling pathway. We investigated associations between HCV and HIV-NRD and between HCV and single-nucleotide polymorphisms (SNPs) in the IL-10 receptor 1 (IL10R1) gene.
Methods. Logistic and Cox regression analysis were used to analyze risk factors for HIV-NRD in 1576 HIV-positive patients who did not have an ocular opportunistic infection at enrollment. Median follow-up was 4.9 years (interquartile range, 2.4–8.8 years). Four IL10R1 SNPs were examined in a subset of 902 patients.
Results. The group included 290 patients with chronic HCV infection, 74 with prior infection, and 1212 with no HCV markers. There were 244 prevalent cases of HIV-NRD and 263 incident cases (rate = 3.9/100 person-years). In models adjusted for demographics, HIV treatment and status, liver function, and immune status, both the prevalence and incidence of HIV-NRD were significantly higher in patients with chronic HCV infection (odds ratio = 1.54; 95% confidence interval [CI], 1.03–2.31 and hazard ratio = 1.62; 95% CI, 1.13–2.34, respectively), compared to patients with no HCV markers. Chronic HCV was associated with rs2228055 and 2 additional IL-10R1 SNPs expected to reduce IL-10 signaling. HIV-NRD was not significantly associated with these SNPs.
Conclusions. HCV is a possible risk factor for HIV-NRD. Genetic analysis suggests that alterations in the IL-10 signaling pathway may increase susceptibility to HIV-NRD and HCV infection. Inflammation may link HCV and HIV-NRD.
doi:10.1093/cid/cit550
PMCID: PMC3814824  PMID: 24081683
AIDS; hepatitis C virus; HIV-associated neuroretinal disorder; cytomegalovirus retinitis; HIV-1
2.  MELD score and antibiotics use are predictors of length of stay in patients hospitalized with hepatic encephalopathy 
BMC Gastroenterology  2014;14(1):185.
Background
Hepatic encephalopathy (HE) represents a significant burden to the healthcare system. The aim of this study was to determine factors influencing the hospital length of stay among patients hospitalized with HE.
Methods
A data warehouse query was performed to identify 316 patients with a first hospitalization during which HE occurred, between April 2010 and February 2012. Baseline and hospitalization characteristics were collected with IRB approval. A negative binomial multivariable model was used to control for potential confounders on the length of hospitalization.
Results
Median age was 59 years, and 60.4% of admitted patients were male. The median MELD score was 22 (IQR: 17-28). Median length of stay was 8 days (IQR: 3.25-14.25). After controlling for MELD score, female gender (2.2 days; p = 0.04), being initially admitted for a reason other than HE (liver-related: 7.6 days; p < 0.01 and non liver-related 10.7 days; p < 0.01) and receiving antibiotics other than rifaximin (10.5 days; p < 0.01) were associated with longer length of stay whereas hepatitis C (-3.1 days; p < 0.01) was associated with a shorter length of stay.
Conclusions
MELD score, gender, use of antibiotics other than rifaximin, reason for admission and hepatitis C are predictors readily available in clinic that can help identify patients at risk for longer length of stay.
doi:10.1186/1471-230X-14-185
PMCID: PMC4287486  PMID: 25326084
Hepatic encephalopathy; Length of stay; MELD score
3.  GENETIC ANALYSIS OF INTERFERON INDUCED THYROIDITIS (IIT): EVIDENCE FOR A KEY ROLE FOR MHC AND APOPTOSIS RELATED GENES AND PATHWAYS 
Journal of autoimmunity  2013;44:61-70.
Autoimmune thyroid diseases (AITD) have become increasingly recognized as a complication of interferon-alpha (IFNα) therapy in patients with chronic Hepatitis C virus (HCV) infection. Interferon-induced thyroiditis (IIT) can manifest as clinical thyroiditis in approximately 15% of HCV patients receiving IFNα and subclinical thyroiditis in up to 40% of patients, possibly resulting in either dose reduction or discontinuation of IFNα treatment. However, the exact mechanisms that lead to the development of IIT are unknown and may include IFNα-mediated immune-recruitment as well as direct toxic effects on thyroid follicular cells. We hypothesized that IIT develops in genetically predisposed individuals whose threshold for developing thyroiditis is lowered by IFNα. Therefore, our aim was to identify the susceptibility genes for IIT. We used a genomic convergence approach combining genetic association data with transcriptome analysis of genes upregulated by IFNα. Integrating results of genetic association, transcriptome data, pathway, and haplotype analyses enabled the identification of 3 putative loci, SP100/110/140 (2q37.1), HLA (6p21.3), and TAP1 (6p21.3) that may be involved in the pathogenesis of IIT. Immune-regulation and apoptosis emerged as the predominant mechanisms underlying the etiology of IIT.
doi:10.1016/j.jaut.2013.04.002
PMCID: PMC3740053  PMID: 23683877
Interferon; thyroiditis; autoimmunity; Thyroid
4.  SILEN-C3, a Phase 2 Randomized Trial with Faldaprevir plus Pegylated Interferon α-2a and Ribavirin in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients 
Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143–2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).
doi:10.1128/AAC.02497-13
PMCID: PMC4068493  PMID: 24709256
5.  Rapid Progression to Decompensated Cirrhosis, Liver Transplant, and Death in HIV-Infected Men After Primary Hepatitis C Virus Infection 
Four men from a cohort of HIV-infected men who did not achieve cure after primary hepatitis C virus infection developed decompensated cirrhosis within 17 months to 6 years after infection, with subsequent rapid progression to liver transplant and death.
Background. We and others have shown that primary hepatitis C (HCV) infection in men infected with human immunodeficiency virus (HIV) causes early-onset liver fibrosis; however, little is known about the long-term natural history of the liver disease in these HIV-infected men.
Methods. We followed a cohort of HIV-infected men with primary HCV infection in New York City.
Results. Four men who were not cured after their primary HCV infection developed decompensated cirrhosis within 17 months to 6 years after primary HCV infection. Three died within 8 years of primary HCV infection, and 1 survived after liver transplant done 2 years after primary HCV infection. Three of the 4 men had AIDS at the time of primary HCV infection, and the most rapid progression occurred in the 2 men with the lowest CD4 counts at the time of HCV infection. Liver histopathology was most consistent with HCV-induced damage even though some had exposures to other potential hepatotoxins.
Conclusions. Primary HCV infection resulted in decompensated cirrhosis and death within 2–8 years in 4 HIV-infected men. The rapid onset of fibrosis due to primary HCV infection in HIV-infected men cannot therefore be considered benign. The rate of continued progression to liver failure may be proportional to the degree of underlying immunocompromise caused by HIV infection. More research is needed to better define the mechanisms behind accelerated liver damage.
doi:10.1093/cid/cis1206
PMCID: PMC3588118  PMID: 23264364
liver failure; primary acute hepatitis C infection; HIV infection/AIDS; immunocompromise; men who have sex with men
7.  Direct-Acting Antiviral Agents in Patients with Hepatitis C Cirrhosis 
Gastroenterology & Hepatology  2012;8(11):727-765.
Patients with cirrhosis who are infected with hepatitis C virus (HCV) are the most in need of antiviral treatment. Virologic cure improves fibrosis and quality of life while reducing liver-related morbidity and mortality. In mid-2011, the addition of direct-acting antiviral agents (DAAs)—the protease inhibitors boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex)—to pegylated interferon α-2a/b and ribavirin revolutionized the treatment of HCV infection by increasing cure rates across all fibrosis scores in patients with genotype 1 HCV infection. However, patients with advanced fibrosis or cirrhosis are the most difficult to treat, and the addition of DAAs increases treatment side effects as well as potency. Five phase III DAA trials have been published to date, but they contain limited data on patients with cirrhosis. This review will examine the available data and will describe the evolution of HCV therapy in patients with cirrhosis from the standard-of-care therapy of the past decade into the new era of DAAs.
PMCID: PMC3966169  PMID: 24672409
Chronic hepatitis C virus infection; cirrhosis; protease inhibitors; direct-acting antiviral agents; boceprevir; telaprevir; sustained virologic response; anemia; decompensation
8.  Mortality in Hepatitis C Virus–Infected Patients With a Diagnosis of AIDS in the Era of Combination Antiretroviral Therapy 
Chronic hepatitis C increased mortality by approximately 50% in patients with Centers for Disease Control and Prevention–defined AIDS, despite the competing mortality risks in these patients. About 20% of the deaths were liver-related, suggesting that greater hepatitis C virus awareness and treatment could increase survival.
Background. Before the introduction of combination antiretroviral therapy (cART), patients infected with the human immunodeficiency virus (HIV) rarely died of liver disease. In resource-rich countries, cART dramatically increased longevity. As patients survived longer, hepatitis C virus (HCV) infection became a leading cause of death; however, because patients with AIDS continue to have 5-fold greater mortality than non-AIDS patients, it is unclear whether HCV infection increases mortality in them.
Methods. In this investigation, which is part of the Longitudinal Studies of the Ocular Complications of AIDS, plasma banked at enrollment from 2025 patients with AIDS as defined by the Centers for Disease Control and Prevention were tested for HCV RNA and antibodies.
Results. Three hundred thirty-seven patients had HCV RNA (chronic infection), 91 had HCV antibodies and no HCV RNA (cleared infection), and 1597 had no HCV markers. Median CD4+ T-cell counts/µL were 200 (chronic), 193 (cleared), and 175 (no markers). There were 558 deaths. At a median follow-up of 6.1 years, patients with chronic HCV had a 50% increased risk of mortality compared with patients with no HCV markers (relative risk [RR], 1.5; 95% confidence interval [CI], 1.2–1.9; P = .001) in an adjusted model that included known risk factors. Mortality was not increased in patients with cleared infection (RR, 0.9; 95% CI, .6–1.5; P = .82). In patients with chronic HCV, 20.4% of deaths were liver related compared with 3.8% in patients without HCV.
Conclusions. Chronic HCV infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS, despite competing risks. Effective HCV treatment may benefit HIV/HCV-coinfected patients with AIDS.
doi:10.1093/cid/cis404
PMCID: PMC3369565  PMID: 22534149
9.  Insulin Resistance Predicts Retreatment Failure in an Efficacy Study of Peginterferon-α-2a and Ribavirin in HIV/HCV Co-infected Patients 
Journal of hepatology  2010;54(1):41-47.
Background and Aims
Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. To evaluate safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response including insulin resistance, and the relationship between insulin resistance and liver histology.
Methods
This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48 weeks. Serum HCV RNA was measured 24 weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR >2. Correlations between baseline insulin resistance and steatosis and/or cirrhosis were determined.
Results
Sustained virological response was achieved by 14/96 (15%) patients. Of those with HOMA-IR <2, 35% (6/17) achieved sustained virological response vs 14% (15/36) of those with HOMA-IR between 2–4 and 7% (3/41) of those with HOMA-IR >4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95%CI 0.05–0.64, p=0.009, and AOR 0.36; 95%CI 0.14–0.93, p=0.04, respectively). Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% and 2 patients died of unrelated cause.
Conclusions
In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those without insulin resistance are significantly more likely to achieve sustained virological response.
doi:10.1016/j.jhep.2010.06.025
PMCID: PMC2994950  PMID: 20974502
Insulin resistance; hepatitis C virus; chronic; HIV; retreatment; antiviral therapy; pegylated interferon alfa-2a; ribavirin
10.  Short Communication: Inadequate Vitamin D Exacerbates Parathyroid Hormone Elevations in Tenofovir Users 
Abstract
Parathyroid hormone (PTH) elevations are associated with reduced bone mineral density and adverse health outcomes and have been reported in patients with HIV infection. We aimed to examine the impact of vitamin D status and tenofovir (TDF) use on PTH levels among HIV-infected patients receiving combination antiretroviral therapy (cART). Demographics, medication and supplement use, and clinical data, including 25-hydroxyvitamin D [25(OH)D] and PTH, were collected on 45 HIV-infected men on ART. Suboptimal vitamin D status was defined as 25(OH)D < 30 ng/ml. The relationship between antiretroviral agents, suboptimal 25(OH)D, and PTH levels was examined. Among subjects with suboptimal vitamin D status, PTH values greater than or equal to the ULN (87 pg/ml) were more common among TDF users than nonusers: 41% versus 0% (p = 0.018); and median PTH was higher in TDF users: 80 pg/ml versus 55 pg/ml (p = 0.02). Among TDF users, PTH was higher in the group with suboptimal 25(OH)D (p = 0.045). Multivariable linear regression showed that PTH was independently and directly related to TDF use (p = 0.017) and inversely related to 25(OH)D (p = 0.017). PTH was not related to the estimated glomerular filtration rate (p = 0.9). In this cross-sectional study of HIV-infected men on ART, the use of TDF and the level of 25(OH)D were independently associated with PTH levels. Because TDF is a potent and widely used antiretroviral drug, information about cofactors that may exacerbate its side effects is of significant clinical value.
doi:10.1089/aid.2009.0308
PMCID: PMC2957627  PMID: 20672993
11.  Hepatitis C Patients' Self-reported Adherence to Pegylated Interferon and Ribavirin 
Background
Prior research on adherence to Hepatitis C treatment has documented rates of dose reductions and early treatment discontinuation, but little is known about patients' dose-taking adherence.
Aims
To assess the prevalence of missed doses of pegylated interferon and ribavirin and examine the correlates of dose-taking adherence in clinic settings.
Methods
180 patients on treatment for Hepatitis C (23% co-infected with HIV) completed a cross-sectional survey at the site of their Hepatitis C care.
Results
Seven percent of patients reported missing at least one injection of pegylated interferon in the last four weeks and 21% reported missing at least one dose of ribavirin in the last 7 days. Dose-taking adherence was not associated with HCV viral load.
Conclusions
Self-reported dose nonadherence to Hepatitis C treatment occurs frequently. Further studies of dose nonadherence (assessed by method other than self-report) and its relationship to HCV virologic outcome are warranted.
PMCID: PMC2891196  PMID: 19086329
Adherence; HCV; HIV; co-infection; interferon; ribavirin
12.  Hepatic profile analyses of tipranavir in Phase II and III clinical trials 
Background
The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.
Methods
Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.
Results
Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade ≤ 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.
Conclusion
Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline.
Trial registration
US-NIH Trial registration number: NCT00144170
doi:10.1186/1471-2334-9-203
PMCID: PMC2803791  PMID: 20003457
13.  Hepatitis B 
Gastroenterology & Hepatology  2007;3(9):724-726.
PMCID: PMC3104263  PMID: 21960885

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