Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the safety, maximum tolerated dose, and preliminary efficacy of concomitant interferon-alpha and zidovudine therapy in AIDS-related Kaposi's sarcoma (KS), 56 patients with biopsy-proven KS and documented human immunodeficiency virus type 1 (HIV) infection were enrolled into a phase I study. Interferon-alpha was given intramuscularly at a dose of 9, 18, or 27 mu once a day and zidovudine was administered as 100 or 200 mg every 4 h for 8 weeks followed by a 48-week maintenance period. The major toxicities were anemia, neutropenia, and hepatotoxicity. Neutropenia was dose limiting with 1,200 mg of zidovudine/day and the lowest dose of interferon-alpha (9 mu/day). Hepatotoxicity was dose limiting with 27 mu of interferon and 600 mg of zidovudine/day. Cumulative dose-related anemia or neutropenia was not seen during long-term follow-up. The maximum tolerated doses for the combination were defined as 18 mu daily for interferon-alpha and 600 mg daily for zidovudine. Variable changes in CD4 lymphocytes occurred during the first 8 weeks of therapy. At higher doses of the combination, sustained increases in median CD4 lymphocyte numbers were noted (p less than 0.001). In HIV antigenemic patients, progressive antigen suppression was seen with increasing doses of the combination (p less than 0.005). The overall antitumor response rate was 47%. Tumor regression was associated with better survival benefits (p less than 0.001) and a pretreatment CD4 cell count greater than or equal to 200 cells/mm3 (p = 0.01). In conclusion, intermediate doses of interferon-alpha and lower doses of zidovudine appear to be relatively well tolerated and associated with disease improvement, including survival benefits.
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PMID:A phase I study of recombinant human interferon-alpha 2a or human lymphoblastoid interferon-alpha n1 and concomitant zidovudine in patients with AIDS-related Kaposi's sarcoma. 167 May 85

The prevalence of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection ranges from nearly 30% to over 50%, depending on the population. Shared modes of transmission and the success of current antiretroviral regimens have contributed to the emergence of HCV as a significant pathogen in the HIV-positive population. HIV coinfection appears to worsen HCV infection, with studies showing more severe fibrosis, a higher frequency of cirrhosis, and increased deaths from liver disease. HIV coinfection may also increase the rate of maternal-fetal transmission of HCV. Similarly, studies suggest a more rapid progression to AIDS or death for HCV genotypes 1a and 1b than for other genotypes in HIV-infected patients with hemophilia. Highly active antiretroviral therapy (HAART), such as HIV protease inhibitors, has no effect on HCV infection and may transiently increase ALT, AST, and hepatitis C viral load. Hepatotoxicity associated with HAART may or may not be related to the presence of HCV and may depend on the specific agents used. Data suggest that treating chronic hepatitis C in HIV-co-infected patients can decrease fibrosis, increase T-cell responsiveness to HCV antigens, and decrease the rate of fatal hepatomas. Interferon alpha may provide sustained biochemical or virologic responses in HIV/HCV-coinfected patients. The combination of interferon-alpha and ribavirin may also be a treatment option but is more complex, and additional research is needed. Treating HCV infection in HIV/HCV-coinfected individuals may help lower the hepatitis C viral load and permit treatment with protease inhibitors.
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PMID:Hepatitis C virus and human immunodeficiency virus: clinical issues in coinfection. 1065 64

Hepatotoxicity was investigated, using plasma collected before and during treatment, in 16 human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected patients who responded to highly active antiretroviral therapy (HAART), during a retrospective longitudinal study. Eleven patients experienced hepatotoxicity (i.e., a >3-fold increase in alanine aminotransferase level) while receiving HAART, including 4 patients with clinical hepatitis. Control subjects were 5 patients without hepatotoxicity. Markers of HCV-specific immune responses (HCV core-specific immunoglobulin G [IgG] antibody), T cell activation (soluble [s] CD26 dipeptidyl peptidase IV [DPP IV] enzyme activity), and inflammation (nitrate/nitrite and soluble tumor necrosis factor receptor I [sTNFRI] levels) were correlated with liver damage and immune reconstitution. All patients with hepatotoxicity had increased HCV core-specific IgG antibody and sCD26 (DPP IV) activity but did not have increased nitrate/nitrite or sTNFRI levels. Hepatotoxicity without clinical hepatitis was associated with increased CD8 T cell counts. Thus, hepatotoxicity in HIV-HCV-coinfected patients who respond to HAART is associated with increased HCV-specific immune responses and T cell activation.
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PMID:Association of increased hepatitis C virus (HCV)-specific IgG and soluble CD26 dipeptidyl peptidase IV enzyme activity with hepatotoxicity after highly active antiretroviral therapy in human immunodeficiency virus-HCV-coinfected patients. 1240 69

Hepatotoxicity has been demonstrated to be associated with antiretroviral therapy. Previous studies have included small numbers of patients and, thus, were unable to produce adequate statistical comparisons. I review data analyses from the Amsterdam, CHORUS, ICONA and Target studies (5133 patients), which were conducted by a number of investigators. There were differences between the cohorts with respect to the incidence of viral hepatitis and definitions of hepatotoxicity used. However, in all cohorts, hepatotoxicity in human immunodeficiency virus type 1-infected patients was significantly associated with coinfection with viral hepatitis. In 3 cohorts, elevated baseline alanine aminotransferase levels predicted subsequent hepatotoxicity. Overall, there was a low incidence of long-term hepatotoxicity in these cohorts and no consistent association between a particular drug or drug class. Nevirapine use within the first 12 weeks after initiation of therapy with this drug and ritonavir use are associated with increased risk of antiretroviral-associated hepatotoxicity.
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PMID:Liver toxicity in epidemiological cohorts. 1498 75

Abnormalities in hepatic function have become one of the most common complications occurring among human immunodeficiency virus (HIV)-infected individuals receiving highly active antiretroviral therapy (HAART), and liver disease has become an increasingly important cause of morbidity and mortality in HIV-infected patients. We present a case of a patient with HIV infection and hepatotoxicity that exemplifies the complications currently observed during the treatment of such patients. Hepatotoxicity can be a result of several factors, including a direct effect of HAART, substance abuse, and coinfection with either hepatitis C virus (HCV) or hepatitis B virus. Imaging studies may be helpful in determining the etiology; however, a liver biopsy is often necessary to be able to more accurately determine the relative contributions of different processes. Although coinfection with HCV and HIV has become a common clinical problem, optimal treatment of such patients remains to be defined and must be individualized to maximize benefit and tolerance.
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PMID:HIV Infection, hepatitis C infection, and HAART: hard clinical choices. 1524 74

Human immunodeficiency virus-infected patients on antiretroviral drug therapy frequently experience hepatotoxicity, the underlying mechanism of which is poorly understood. Hepatotoxicity from other compounds such as bosentan and troglitazone has been attributed, in part, to inhibition of hepatocyte bile acid excretion. This work tested the hypothesis that antiretroviral drugs modulate hepatic bile acid transport. Ritonavir (28 microM), saquinavir (15 microM), and efavirenz (32 microM) inhibited [(3)H]taurocholate transport in bile salt export pump expressing Sf9-derived membrane vesicles by 90, 71, and 33%, respectively. In sandwich-cultured human hepatocytes, the biliary excretion index (BEI) of [(3)H]taurocholate was maximally decreased 59% by ritonavir, 39% by saquinavir, and 20% by efavirenz. Likewise, in sandwich-cultured rat hepatocytes, the BEI of [(3)H]taurocholate was decreased 100% by ritonavir and 94% by saquinavir. Sodium-dependent and -independent initial uptake rates of [(3)H]taurocholate in suspended rat hepatocytes were significantly decreased by ritonavir, saquinavir, and efavirenz. [(3)H]Taurocholate transport by recombinant NTCP and Ntcp was inhibited by ritonavir (IC(50) = 2.1 and 6.4 microM in human and rat, respectively), saquinavir (IC(50) = 6.7 and 20 microM, respectively), and efavirenz (IC(50) = 43 and 97 microM, respectively). Nevirapine (75 microM) had no effect on bile acid transport in any model system. In conclusion, ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibited both the hepatic uptake and biliary excretion of taurocholate.
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PMID:Ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibit bile acid transport in human and rat hepatocytes. 1672 Jul 53

Human immunodeficiency virus/hepatitis C virus (HIV/HCV) co-infection has emerged as a leading cause of liver morbidity in the last two decades. Liver failure is also frequently a cause of death in HIV/HCV co-infected patients. Highly active antiretroviral treatment (HAART) has revolutionized the HIV treatment, leading to a significantly decreased morbidity, prolonged survival, and an overall better outcome of HIV infection. Hepatotoxicity associated with antiretroviral treatment, however, has been recognized as one of the serious complications of the treatment. The effects of HIV infection on the natural history and progression of HCV-associated chronic liver disease that had been well documented in the pre-HAART treatment era have been changing, and there are now many indications that HIV/HCV co-infection should be recognized as an evolving and a challenging disease entity.
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PMID:HIV/HCV co-infection: histopathologic findings, natural history, fibrosis, and impact of antiretroviral treatment: a review article. 1749 43

Latent tuberculosis infection (LTBI) is a condition in which a person is infected with Mycobacterium tuberculosis, but does not currently have active tuberculosis disease. An estimated 10 to 15 million persons in the United States have LTBI. Because 5 to 10 percent of persons with LTBI are at risk of progressing to active disease, identification and treatment of LTBI are essential for the elimination of tuberculosis. Screening is recommended for high-risk persons, including immigrants; residents and employees of congregate living facilities; and persons infected with human immunodeficiency virus. Targeted tuberculin skin testing remains the most acceptable method of LTBI screening. New tests are being developed, the most promising of which are in vitro interferon-gamma release assays. All screened persons found to have LTBI should be offered treatment, regardless of age. Before initiating treatment, active tuberculosis must be ruled out by patient history, physical examination, and chest radiography. The treatment of choice for LTBI is isoniazid for nine months. Hepatotoxicity is the most severe adverse effect. Isoniazid should be discontinued if transaminase levels are greater than three times the upper limit of normal in symptomatic patients or five times the upper limit of normal in asymptomatic patients.
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PMID:Identification and management of latent tuberculosis infection. 1949 83

Kaposi's sarcoma is a vascular tumor linked to the presence of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) and the incidence of which has increased considerably the world over after the onset of the human immunodeficiency virus (HIV) pandemic. Antiretroviral therapy combined with cytotoxic agents has been established as the treatment of choice in the past 10 years. Among chemotherapeutic agents, pegylated liposomal doxorubicin has become the preferred one for patients with HIV-associated Kaposi's sarcoma in Western countries. The drug in this formulation localizes better to the tumor and has higher efficacy. Skin toxicity, mucositis, and leukopenia/neutropenia are the main side effects. Hepatotoxicity and mild cardiotoxicity are observed less frequently. Pegylated liposomal doxorubicin impacts favorably on quality of life. Although cost effective in Western countries, the drug is less so in developing countries.
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PMID:Safety and efficacy of pegylated liposomal doxorubicin in HIV-associated Kaposi's sarcoma. 1977 6

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor frequently used in combination with other antiretroviral agents for highly active antiretroviral therapy (HAART) of patients infected with the human immunodeficiency virus type 1 (HIV-1). However NVP can cause serious, life-threatening complications. Hepatotoxicity is one of the most severe adverse effects, particularly in HIV patients with chronic hepatitis C virus co-infection as these patients can develop liver toxicity after a relatively short course of treatment. However, the mechanism of NVP-associated hepatotoxicity remains unclear. This study sought to investigate the effect of NVP on protein expression in liver cells using a proteomic approach. HepG2 cells were treated or not treated with NVP and proteins were subsequently resolved by two-dimensional gel electrophoresis. A total of 33 differentially regulated proteins were identified, of which nearly 40% (13/33) were mitochondrial proteins. While no obvious differences were observed between NVP treated and untreated cells after staining mitochondria with mitotracker, RT-PCR expression analysis of three mitochondrially encoded genes showed all were significantly up-regulated in NVP treated cells. Mitochondrial dysfunction was observed in response to treatment even with slightly sub-optimal therapeutic treatment concentrations of NVP. This study shows that NVP induces mitochondrial dysregulation in HepG2 cells.
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PMID:Nevirapine induced mitochondrial dysfunction in HepG2 cells. 2883 69


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