Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) infection has emerged as the main cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected individuals, since the introduction of antiretroviral therapy. Coinfection with both viruses may lead to end-stage liver disease (ESLD), including cirrhosis and hepatocellular carcinoma. HCV infection is altered by HIV presence, although the effect of HCV on HIV infection is still controversial. For this reason, HCV screening is recommended in all HIV-infected persons. The final goal of HCV treatment is to eradicate the virus or, in other words, to eliminate the infection, and this objective is especially important in HIV/HCV-coinfected patients, because they have more severe liver disease, achieve less frequently sustained virologic response on treatment, and have limited access to orthotopic liver transplantation with respect to HCV-monoinfected patients. Combination therapy with pegylated interferon-alpha (pegIFN) and ribavirin (RBV) has become the standard treatment for chronic HCV infection. However, when we compare coinfected with monoinfected patients, this regimen has decreased efficacy, and the rate of adverse effects is higher.
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PMID:Update on hepatitis C treatment in HIV-coinfected patients. 1571 8

A significant percentage of human immunodeficiency virus (HIV) -infected individuals are also infected with the hepatitis C virus (HCV). With the much-improved survival of HIV-infected patients through the use of highly active antiretroviral therapy, liver disease caused by coinfection with HCV has emerged as a significant threat to the health and survival of persons with HIV disease. HIV/HCV-coinfected patients with ongoing HIV viremia have a faster rate of HCV-related liver fibrosis progression and a more rapid progression to liver failure or hepatocellular carcinoma than HCV-monoinfected persons. In contrast to the deleterious effect of HIV on HCV-related liver disease, most studies have shown that HCV does not influence progression of HIV infection to AIDS or death. HCV therapy with peginterferon alfa (2a or 2b) plus ribavirin can achieve a sustained viral response in HIV/HCV-coinfected patients of up to 38% in HCV genotype 1 and up to 73% in genotypes 2 and 3. The safety profile is largely similar to therapy in HIV-monoinfected patients, but there is a higher incidence of mitochondrial toxicity in patients taking didanosine or stavudine and of anemia in patients taking zidovudine. There is no proven anti-HCV therapy for HIV/HCV-coinfected patients with end-stage liver disease (ESLD). Liver transplantation is being investigated as a potential therapeutic option for HIV-infected individuals with ESLD, and initial reports are encouraging. Given that pegylated interferon and ribavirin have been shown to be safe and effective for HIV/HCV coinfection as well as HCV monoinfection, all HIV/HCV-coinfected patients should be evaluated for therapy.
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PMID:Treatment of chronic hepatitis C in human immunodeficiency virus/hepatitis C virus-coinfected patients in the era of pegylated interferon and ribavirin. 1573 96

Congenital and neonatal viral infections usually display their acute manifestations in highly recognisable ways, for example, congenital rubella, cytomegalovirus (CMV), varicella, human immunodeficiency (HIV) and herpes simplex virus (HSV) infection. By contrast, congenital hepatitis B virus (HBV) infection may go undetected for years. Some of these are preventable, but what is not immediately apparent is that the long-term consequences are being prevented as well. The long-term consequences of congenital and neonatal infections include endocrine, immunological and cardiovascular disease, deafness, visual problems, intellectual handicap and cerebral palsy. With the survival of HIV-infected infants into adulthood the long-term consequences will soon be described. Maternally and neonatally transmitted HBV infection predisposes to carriage, liver cirrhosis and hepatocellular carcinoma in young adults. Neonatal HBV vaccination prevents adult cancer. Acquired viral infections may predispose to subsequent lung disease, malabsorption, fertility problems or neurological disability. In the prevention of acquired rubella, varicella, HBV, influenza, poliovirus, measles and hepatitis A, one should mention the added bonus of preventing secondary cases by preventing transmission from infants and children to other children and adults. Preventing paediatric HSV, HBV and HIV infection in females may even be preventing subsequent transmission to future generations. Turning to paediatric bacterial infections, vaccinating infants and young children against pertussis could not only prevent transmission to older children and adults but also break the cycle, which then transmits from adults back to infants and young children. There is evidence that disease in older age groups, including adults, has been prevented by virtue of herd immunity from paediatric vaccination, e.g. Neisseria meningitidis Group C and Streptococcus pneumoniae. The add-on benefits for other generations, including for adults, arising from the prevention of paediatric infections are considerable.
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PMID:Paediatric infections: prevention of transmission and disease--implications for adults. 1575 76

The expression of manganese superoxide dismutase (MnSOD) is regulated by agents associated with cancer development. It has been shown that infection with the human immunodeficiency virus type 1 (HIV-1) is associated with the development of liver cancer and that the transactivating transcriptional factor (Tat) of human HIV-1 reduces the expression of MnSOD in several cell types. However, the role of Tat in the expression of MnSOD in hepatocellular carcinoma is unknown. Furthermore, the precise mechanisms whereby Tat suppresses MnSOD expression in hepatocellular carcinoma cells remain unclear. In this report, we build on our original observations that Tat changes the distribution of Sp family members on the MnSOD promoter, which accounts for Tat-dependent changes in basal expression. In hepatic cells, Tat expression upregulates Sp1/Sp3, which play different roles in regulating MnSOD transcription. While overexpression of Sp1 stimulates, overexpression of Sp3 represses transcriptional activity. The transcription repression effect of Sp3 is not due to Sp3 competing for the binding site with Sp1 because only the full-length Sp3 but not the truncated Sp3 suppresses MnSOD promoter activity. These findings suggest a novel mechanism by which Tat modulates the repression of the MnSOD gene and establish a link between HIV infection and liver cancer.
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PMID:Different roles of Sp family members in HIV-1 Tat-mediated manganese superoxide dismutase suppression in hepatocellular carcinoma cells. 1586 7

Beta-D-2',3'-dideoxy-3'-oxa-5-fluorocytidine (D-FDOC) is an effective inhibitor of human immunodeficiency virus 1 (HIV-1) and HIV-2, simian immunodeficiency virus, and hepatitis B virus (HBV) in vitro. The purpose of this study was to evaluate the intracellular metabolism of d-FDOC in human hepatoma (HepG2), human T-cell lymphoma (CEM), and primary human peripheral blood mononuclear (PBM) cells by using tritiated compound. By 24 h, the levels of D-FDOC-triphosphate (D-FDOC-TP) were 2.8 +/- 0.4, 6.7 +/- 2.3, and 2.0 +/- 0.1 pmol/10(6) cells in HepG2, CEM, and primary human PBM cells, respectively. Intracellular D-FDOC-TP concentrations remained greater than the 50% inhibitory concentration for HIV-1 reverse transcriptase for up to 24 h after removal of the drug from cell cultures. In addition to d-FDOC-monophosphate (D-FDOC-MP), -diphosphate (D-FDOC-DP), and -TP, D-FDOC-DP-ethanolamine and d-FDOC-DP-choline were detected in all cell extracts as major intracellular metabolites. D-FDOC was not a substrate for Escherichia coli thymidine phosphorylase. No toxicity was observed in mice given D-FDOC intraperitoneally for 6 days up to a dose of 100 mg/kg per day. Pharmacokinetic studies in rhesus monkeys indicated that D-FDOC has a t(1/2) of 2.1 h in plasma and an oral bioavailability of 38%. The nucleoside was excreted unchanged primary in the urine, and no metabolites were detected in plasma or urine. These results suggest that further safety and pharmacological studies are warranted to assess the potential of this nucleoside for the treatment of HIV- and HBV-infected individuals.
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PMID:Pharmacology and pharmacokinetics of the antiviral agent beta-D-2',3'-dideoxy-3'-oxa-5-fluorocytidine in cells and rhesus monkeys. 1598 Mar 24

Principally, because of the association of the chronic carrier state with the development of cirrhotic liver disease and hepatocellular carcinoma, chronic hepatitis B infection is a public health problem of global significance. In the main, therapy for chronic hepatitis B is limited to the use of alpha interferon for a limited number of chronic hepatitis B virus (HBV) carriers who have chronic hepatitis with active viral replication. The development of antiviral nucleoside analogues for the herpes viruses and human immunodeficiency virus (HIV) has resulted in the identification of several compounds which also have activity against HBV. Unfortunately, these agents have not been associated with the clearance of hepatitis B infection, but rather only the suppression of active infection while the patient is receiving medication. In addition, the development of drug-resistance to these agents by the virus will most likely limit their long-term efficacy. Gene therapy has recently been applied to HBV both in vitro and in vivo. This has included the use of antisense oligodeoxynucleotides and RNA, ribozymes, dominant negative mutants and therapeutic HBV vaccines. These newer therapeutic modalities may hold promise as effective treatments for chronic hepatitis B, but to date, have been limited by the problem of delivery to the target cell population or infected organ in vivo. Combination nucleoside analogue therapy may also provide an important treatment modality for chronic hepatitis B, although this will require further investigation.
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PMID:New therapeutic strategies in the treatment of hepatitis B virus infection. 1599 79

Hepatitis C virus is a leading cause of chronic liver disease, with over 170 million people infected worldwide. It is also the leading indication for liver transplantation. Complications from chronic hepatitis C infection include cirrhosis, hepatic decompensation, and hepatocellular carcinoma. As a result, treatment strategies to prevent such complications have been widely researched, although many questions remain unanswered. To date, the standard therapy for chronic hepatitis C infection is the combination of peginterferon and ribavirin. Treatment strategies differ based on factors such as genotype and liver biopsy results. Other strategies must be considered for special groups, such as patients with acute hepatitis C infection, hepatitis C/human immunodeficiency virus (HIV) coinfection, and prior nonresponse to interferon or relapse after its use. The goal of therapy is to achieve a sustained virologic response (ie, no detectable hepatitis C ribonucleic acid 6 months after completion of therapy). The substantial adverse effects associated with both interferon alfa and ribavirin often make it difficult for patients to continue with their therapies.
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PMID:Treatment of hepatitis C. 1608 69

Before the mid-1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV-1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV-seropositive patients, age 13-88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross-sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV-1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV-1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV-1-positive participants had > or = 200 CD4+ cells microL(-1), only 59% were on HAART. HIV-1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti-HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV-1-positive than HIV-1-negative participants (85% vs. 70%, P < 0.0001). HIV-1-positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV-negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self-reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non-Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV-1, HCV or both.
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PMID:Prevalence of conditions associated with human immunodeficiency and hepatitis virus infections among persons with haemophilia, 2001-2003. 1612 97

Hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is not uncommon as a result of similar routes of infection. Patients who are coinfected represent a unique group with diverse serologic profiles. Combined chronic hepatitis B and C leads to more severe liver disease and an increased risk of hepatocellular carcinoma. Furthermore, coinfected patients represent a treatment challenge. No standard recommendations exist for treatment of viral hepatitis due to dual HBV/HCV infection, and therefore treatment must be individualized based on patient variables such as serologic and virologic profiles, patient's prior exposure to antiviral treatment, and the presence of other parenterally transmitted viruses such as hepatitis D virus and human immunodeficiency virus. The natural history and treatment of patients with HBV and HCV coinfection is reviewed.
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PMID:Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection. 1615 99

Chronic infection with hepatitis C virus (HCV) is associated with liver cirrhosis that often leads to hepatic failure and hepatocellular carcinoma (HCC). HCV infection has become a global health threat and the main cause of adult liver transplants in developed nations. Current approved anti-HCV therapies (interferon and pegylated interferon alone or in combination with ribavirin) are not effective in eliminating the viral infection in a significant population of patients (e.g., those infected with HCV genotype 1). Furthermore, these therapies are plagued with many undesirable side effects. Therefore, the HCV epidemic represents a huge unmet medical need that has triggered intensive research efforts towards the development of more effective drugs. Given its essential role in the process of HCV replication, the viral NS3/4A serine protease is arguably the most thoroughly characterized HCV enzyme and the most intensively pursued anti-HCV target for drug development. This is further fueled by the successful use of small-molecule inhibitors of the human immunodeficiency virus (HIV) viral protease, which have had an impressive effect on HIV-related morbidity and mortality, offering hope that analogous drugs might also have a similar impact against HCV. Here, we review the recent progress and development of small-molecule inhibitors of the HCV NS3/4A protease. In particular, we focus on the discovery of VX-950, the latest HCV NS3-4A protease inhibitor to be advanced to clinical studies. While the challenges of designing potent inhibitors of the viral protease have been solved, as highlighted by BILN 2061 and VX-950, it is still too early to determine whether these efforts will eventually yield promising drug candidates. For the emerging small-molecule HCV inhibitors, viral resistance will likely be a big problem. Thus, combination therapy of different drugs with different targets/mechanisms will be necessary to effectively inhibit HCV replication. It is also hoped that a detail characterization of how the resistance mutations that affect NS3 inhibitor binding may provide useful information for the design of inhibitors with the potential to treat resistant viruses that may arise during chronic HCV infection.
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PMID:Discovery of small-molecule inhibitors of HCV NS3-4A protease as potential therapeutic agents against HCV infection. 1618 Nov 35


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