Faculty Bibliography
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301
Expert opinion on drug metabolism & toxicology. 2013:9(12):1647-57.DOI: 10.1517/17425255.2013.840290
The pharmacokinetic evaluation of boceprevir for treatment of hepatitis C virus
INTRODUCTION: Boceprevir is an NS3/NS4A serine protease inhibitor that was approved for use in Hepatitis C virus (HCV) genotype 1 patients by the US Food and Drug Administration (FDA) in May 2011. The approval of this protease inhibitor marked a major paradigm shift in the treatment of HCV, as it was one of the first of many new small molecules specifically designed and approved for HCV. AREAS COVERED: In this article, the authors summarize boceprevir's pharmacokinetic and pharmacodynamic properties. In addition, they review Phase II and III trials of boceprevir as well as its clinical efficacy, dosing and safety. EXPERT OPINION: Boceprevir is a potent protease inhibitor for the treatment of genotype 1 HCV. It has a well-tolerated side-effect profile and increases the likelihood of SVR in naive and previously treated patients. The impending release of newer more efficacious direct-acting antivirals may limit the use of boceprevir for patients infected with HCV.
PMID: 24079600
ISSN: 1742-5255
CID: 897132
Evaluation of hepatitis C virus as a risk factor for HIV-associated neuroretinal disorder
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.
PMCID:3814824
PMID: 24081683
ISSN: 1058-4838
CID: 897142
WHEN TREATMENT IS MITIGATED BY ADVERSE EVENTS: THE ECONOMIC IMPACT OF TREATMENT-ASSOCIATED ADVERSE EVENTS IN CIRRHOTIC NON-RESPONDERS TREATED WITH BOCEPREVIR OR TELAPREVIR AND PEGINTERFERON ALPHA/RIBAVIRIN [Meeting Abstract]
ISI:000326247600155
ISSN: 1524-4733
CID: 2728822
Antiretroviral and anti-hepatitis C virus direct-acting antiviral-related hepatotoxicity
Antiretroviral-related hepatotoxicity occurs commonly in patients with human immunodeficiency virus (HIV). Liver injury ranges from unconjugated hyperbilirubinemia and nodular regenerative hyperplasia to lactic acidosis and toxic hepatitis. Effective antiretroviral therapy has changed coinfected patients' primary morbidities and mortality to chronic liver disease rather than complications from HIV. Treatment for hepatitis C virus (HCV) is strongly encouraged early in all coinfected patients. However, drug-drug interactions must be considered to ensure safe and tolerable use alone or in combination with antiretroviral therapies. The first-generation and newer HCV direct-acting antivirals are promising in coinfected patients, with minimal side effects and hepatotoxicity.
PMID: 24099023
ISSN: 1089-3261
CID: 897152
Novel community-based hepatitis B and C screening program among African immigrants with linkage to care by a culturally-targeted patient navigator [Meeting Abstract]
ISI:000330252203025
ISSN: 0270-9139
CID: 833482
The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future
The Electronic Medical Records and Genomics Network is a National Human Genome Research Institute-funded consortium engaged in the development of methods and best practices for using the electronic medical record as a tool for genomic research. Now in its sixth year and second funding cycle, and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from electronic medical records can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and health-care informatics, particularly for electronic phenotyping, genome-wide association studies, genomic medicine implementation, and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here, we describe the evolution, accomplishments, opportunities, and challenges of the network from its inception as a five-group consortium focused on genotype-phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting toward the implementation of genomic medicine.
PMCID:3795928
PMID: 23743551
ISSN: 1530-0366
CID: 5479322
Genetic analysis of interferon induced thyroiditis (IIT): evidence for a key role for MHC and apoptosis related genes and pathways
Autoimmune thyroid diseases (AITD) have become increasingly recognized as a complication of interferon-alpha (IFNalpha) 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 IFNalpha and subclinical thyroiditis in up to 40% of patients, possibly resulting in either dose reduction or discontinuation of IFNalpha treatment. However, the exact mechanisms that lead to the development of IIT are unknown and may include IFNalpha-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 IFNalpha. 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 IFNalpha. 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.
PMCID:3740053
PMID: 23683877
ISSN: 0896-8411
CID: 897092
Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial
BACKGROUND: Telaprevir (TVR) plus peginterferon-alpha2a (PEG-IFN-alpha2a) and ribavirin substantially increases treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection versus PEG-IFN-alpha2a-ribavirin alone. Its safety and efficacy in patients with HCV and HIV-1 are unknown. OBJECTIVE: To assess the safety and efficacy of TVR plus PEG-IFN-alpha2a-ribavirin in patients with genotype 1 HCV and HIV-1 and to evaluate pharmacokinetics of TVR and antiretrovirals during coadministration. DESIGN: Phase 2a, randomized, double-blind, placebo-controlled study. (ClinicalTrials.gov: NCT00983853). SETTING: 16 international multicenter sites. PATIENTS: 62 patients with HCV genotype 1 and HIV-1 who were HCV treatment-naive and receiving 0 or 1 of 2 antiretroviral regimens were randomly assigned to TVR plus PEG-IFN-alpha2a-ribavirin or placebo plus PEG-IFN-alpha2a-ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-alpha2a-ribavirin. MEASUREMENTS: HCV RNA concentrations. RESULTS: Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-alpha2a-ribavirin during the first 12 weeks. During this period, serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-alpha2a-ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-alpha2a-ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN-alpha2a-ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-alpha2a-ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-alpha2a-ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR. LIMITATION: Small sample size and appreciable dropout rate. CONCLUSION: In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-alpha2a-ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-alpha2a-ribavirin.
PMID: 23685940
ISSN: 0003-4819
CID: 897102
Hepatitis Outreach Network: a practical strategy for hepatitis screening with linkage to care in foreign-born communities
BACKGROUND & AIMS: Many foreign-born persons in the US are at high risk of chronic hepatitis B (HBV) and C (HCV) infections, yet are not aware of their infection, and lack healthcare coverage or linkage to care. METHODS: A unique partnership, the Hepatitis Outreach Network, combines the expertise and resources of the Mount Sinai School of Medicine, the NYC Department of Health and Mental Hygiene, and community-based organizations, to provide education, screening and link to care in communities with high prevalence of chronic viral hepatitis. Comprehensive HBV and HCV screening identifies infected patients, who then receive further evaluation from either local or Mount Sinai physicians, combined with patient-navigators who organize follow-up visits. RESULTS: Of 1603 persons screened, 76 had HBV and 75 had HCV. Importantly, screening for HCV based on traditional risk factors would have missed 67% of those who tested positive. Of the 76 persons with HCV infection, 49 (64%) received a medical evaluation (26 with local providers and 23 at Mount Sinai). Of the 49 HCV-infected persons evaluated, treatment was recommended in 11 and begun in 8 (73%). Of the 76 persons with HBV infection, 43 (57%) received a medical evaluation (31 with local providers and 12 at Mount Sinai). Of the 43 HBV-infected persons evaluated, treatment was recommended and begun in 5 (100%). CONCLUSIONS: Hepatitis Outreach Network has successfully established novel proof of concept for identifying HBV and HCV infections in foreign-born persons through use of several unique elements that effectively link them to care.
PMID: 23333446
ISSN: 0168-8278
CID: 551642
Septic bursitis, a potential complication of protease inhibitor use in hepatitis C virus [Letter]
PMID: 23413416
ISSN: 1058-4838
CID: 897072
