Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zidovudine, a nucleoside analog, was the first agent proved to be effective in the management of human immunodeficiency virus type 1 (HIV-1) infection. After demonstration of zidovudine's in-vitro activity against HIV-1 in 1985, the drug was rapidly evaluated in phase I and phase II clinical trials and was found to be effective in decreasing both mortality and the incidence of opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex; the drug was also found to have a substantial but tolerable toxicity profile. Since the licensure of zidovudine in 1987, an intensive clinical research effort has established the drug's efficacy in the prevention of disease progression in asymptomatic and mildly symptomatic HIV-infected persons and has established the success of lower-dose therapy in patients at all stages of disease. The current recommendation is to use zidovudine at a dose of 500 to 600 mg/d in both symptomatic and asymptomatic persons with CD4 counts of less than 500/mm3. The major toxicities of anemia and neutropenia are less frequent at the lower doses presently used and can be managed by dose reduction or by use of hematopoietic growth factors. The inexorable disease progression seen despite zidovudine therapy and the isolation of clinical strains of HIV-1 resistant to zidovudine in vitro highlight the limitations of prolonged monotherapy with this agent. Although alternative dideoxynucleoside agents (for example, didanosine [dideoxyinosine and zalcitabine dideoxycytidine]) are available for the management of HIV-infected persons, zidovudine remains the cornerstone of antiretroviral therapy. Current research efforts are directed at elucidating the clinical relevance of zidovudine resistance and studying regimens in which zidovudine is used in combination with other agents. This latter approach holds great promise for improving efficacy, limiting toxicity, and perhaps preventing the emergence of viral resistance. For the forseeable future, zidovudine will continue to play a role in the development and in our understanding of antiretroviral therapy.
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PMID:Zidovudine: five years later. 844 32

Reports of in vitro resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine (AZT) have raised concerns about the development of resistance to other dideoxynucleosides in clinical use. To address this, we have developed a screening assay which supports the growth of clinical isolates and have applied this to a series of paired isolates from patients entered into a phase I trial of didanosine (DDI). Thirteen patients (10 with AIDS, 3 with AIDS-related complex) who had been exposed to AZT for a mean of 6.5 months (range, 1 to 13 months) were treated with DDI at 750 mg/day. Paired isolates were obtained pretherapy and after a mean of 58 weeks (range, 21 to 90) of DDI therapy by coculture of peripheral blood mononuclear leukocytes (PBLs) with phytohemagglutinin-stimulated donor PBLs. Isolates were passaged only one additional time in PBLs and then tested in parallel in a microtiter assay with phytohemagglutinin-stimulated donor PBLs as targets. PBLs were infected with 10(5) 50% tissue culture infectious doses per 10(7) cells and exposed to DDI (1 to 50 microM) or AZT (0.01 to 100 microM), and supernatants were assayed for the HIV p24 antigen at 7 days postinfection. Control AZT-susceptible and resistant isolates were included. The median pre- and posttherapy DDI susceptibilities of the 13 pairs of isolates were 10.0 microM (range, 1 to 25 microM) and 17.5 microM (range, 2.5 to 50 microM), respectively (P = 0.036; Wilcoxon signed-rank test). These studies thus indicated that (i) the susceptibility to DDI tends to mildly decrease with drug exposure; (ii) the susceptibility to AZT improves with time off AZT; (iii) baseline susceptibilities to DDI have a wide range, and the CD4 response may correlate with the initial susceptibility; and (iv) a PBL-based microtiter assay is useful for screening clinical isolated for dideoxynucleoside susceptibility profiles.
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PMID:Didanosine and zidovudine resistance patterns in clinical isolates of human immunodeficiency virus type 1 as determined by a replication endpoint concentration assay. 151 Apr 14

3'-Fluoro-3'deoxythymidine (FLT), recombinant soluble CD4 (CD4), and recombinant interferon-alpha (IFN alpha) were evaluated in two- and three-drug regimens against HIV-1 replication in vitro. Peripheral blood mononuclear cells were studied using p24 antigen production as the virologic endpoints. FLT showed 2.5-fold higher efficacy and a similar selectivity index to zidovudine. Drug interactions were evaluated by the median effect principle and the isobologram technique. FLT, CD4, and interferon alpha at noncytotoxic concentrations inhibited HIV-1 synergistically in two- and three-drug combinations with a combination index smaller than one and dose reduction index greater than one. The three-drug regimen provided greater virus suppression than the two-drug regimen. These results suggest that FLT is an alternative agent to AZT for the treatment of HIV infection either as a single agent or in combination with CD4 and/or interferon-alpha.
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PMID:Three-drug synergistic inhibition of HIV-1 replication in vitro by 3'-fluoro-3'-deoxythymidine, recombinant soluble CD4, and recombinant interferon-alpha. 151 12

To investigate the development of a reduced DLCO in patients with HIV-related disease, we studied 474 HIV-seropositive patients and performed serial lung function measurements over 18 months. The mean values of DLCO at presentation were lower in patients with more advanced HIV disease compared with asymptomatic HIV-seropositive patients (DLCO 88% of predicted). When compared with the DLCO in asymptomatic HIV-seropositive patients, the DLCO had reduced values in patients with persistent generalized lymphadenopathy (PGL) (82% of predicted, p less than 0.05), acquired deficiency syndrome-related complex (ARC) (73% predicted, p less than 0.001), nonpulmonary Kaposi's sarcoma (KS) (72% of predicted, p less than 0.001), nonpulmonary complications of AIDS excluding KS (73% of predicted, p less than 0.001), pulmonary KS (63% of predicted, p less than 0.001), pulmonary mycobacterial infection (68% of predicted, p less than 0.05), pyogenic infection (70%, p less than 0.05), acute Pneumocystis carinii pneumonia (PCP; 49%, p less than 0.001), and following recovery from PCP (71%, p less than 0.001). Serial lung function measurements over 18 months revealed no change in DLCO within any patient group, and in particular there was no tendency for a gradual decline. Clinical deterioration due to the development of PCP was associated with a reduction in DLCO. Conversely, in patients recovering from PCP, there was a partial improvement in DLCO over 3 months. Zidovudine (AZT) use did not affect DLCO within any diagnostic group or the recovery in DLCO following PCP. However, cigarette smoking was associated with further reductions in DLCO in all patient groups and with an impaired recovery of DLCO following acute PCP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary function in human immunodeficiency virus infection. A prospective 18-month study of serial lung function in 474 patients. 151 57

A comparison of the activity against human immunodeficiency virus 1 of zidovudine (AZT) and poly I poly C double-stranded RNA both alone and in combination in MT4 cells and primary monocyte/macrophage (M/M) cultures was made. The inhibition of the HIV-induced cytopathic effect or reverse transcriptase production by AZT in MT4 cells was not modified by the combination of the two agents. In contrast, AZT inhibition of reverse transcriptase production in the supernatant of M/M cultures was enhanced by the addition of poly I poly C. The inhibitory effect of the drug combination was more marked in M/M than in MT4 cells, indicating that the evaluation of compounds involving the induction of an antiviral state should be tested not only CD4+ T cells but also in monocyte-macrophages.
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PMID:Anti-human immunodeficiency virus effects of zidovudine in combination with double-stranded RNA poly I poly C in T cells and monocytes-macrophages. 152 May 35

Quantitation of HIV in 115 seropositive individuals was undertaken to evaluate the potential for HIV transmission as a nosocomial infection through the use of medical devices that may come in contact with the peripheral blood of HIV-infected individuals. The virus burden in the peripheral blood was estimated from the level of: plasma HIV p24 antigenemia; plasma viremia; p24 antigen in peripheral blood mononuclear cell (PBMC) lysates as indicators of productive infection; and frequency of latently infected cells. Negligible HIV levels were observed in the plasma and PBMC lysates of the majority of samples except for late-stage patients with certain opportunistic infections and/or lack of zidovudine (AZT) therapy. Some individuals on AZT therapy and at late-stage of disease may show antigenemia without plasma viremia or alternatively, plasma viremia may be observed without plasma antigenemia. PBMC lysate data indicated that the frequency of productively infected cells was less than one in 20,000 PBMCs for the majority of samples irrespective of status on AZT therapy or disease stage. HIV was detected in greater than 95% of the cocultures and within 14 days for most of the samples, again regardless of the stage of disease or status on AZT therapy. The frequency of latently infected cells in this cohort ranged from 125 to 3125 per million PBMCs and was calculated to be as high as 2.5% of the helpter T-cell (CD4+ cell) population in the peripheral blood. The average latently infected cell frequency was 2-3-fold higher in early stage patients not on AZT than in late-stage patients on AZT therapy.
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PMID:Quantitation of human immunodeficiency virus (HIV) with respect to disease stage and zidovudine (AZT) therapy. 152 May 39

To estimate the cumulative incidence of acquired immunodeficiency syndrome (AIDS) in thalassaemia major patients (TMP) human immunodeficiency virus (HIV-1) infected through transfusion, 79 seropositive TMP were studied. At inclusion, mean age was 12.4 +/- 6.6 years; 40 were men; 21 were splenectomized. Centers for Disease Control, 1986 (CDC) stages and prescription of zidovudine were noted at least once a year. Cumulative incidence of AIDS and standard error were calculated using non parametric life table method. Age, sex, acute infection and splenectomy associations with progression to AIDS were tested using Breslow statistic. The median follow-up period was 4 years 11 months. At the end of the study period, 43 TMP were in CDC stage II, 23 in CDC stage III and 13 in CDC stage IV, including seven AIDS cases, of whom three had died. Four subjects died of other causes. Only two patients were treated with AZT prior to the occurrence of AIDS. Rate of progression to AIDS was not associated with acute infection, splenectomy, age, or sex. A cumulative AIDS incidence rate of 1.4% (SE 1.3%) was observed at 3 years and of 9% (SE 4%) at 5 years.
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PMID:Incidence of AIDS in HIV-1 infected thalassaemia patients. European and Mediterranean W.H.O. Working Group on Haemoglobinopathies and Cooleycare. 152 Jun 8

This paper deals with the management of pregnant women with HIV infection. The virus is transmitted by the mother to 20-30 percent of the infants, and therapeutic abortion should be offered to women whose pregnancy does not exceed 26 weeks of amenorrhoea. If pregnancy is pursued, the mother must be investigated for sexually transmitted diseases which are particularly frequent in this population and may have repercussions on the newborn. Pneumocystis carinii pneumonia is the most common opportunistic infection in pregnancy. In case of T4-cell depletion chemotherapy with pentamidine must be instituted. Hygienic and dietetic measures should be applied to avoid listeriosis and toxoplasmosis. Serological tests for toxoplasmosis are necessary in all HIV patients, with chemoprophylaxis in case of increased IgG levels. Thrombocytopenia usually responds to human immunoglobulins. At delivery, there is no need to modify the usual obstetrical procedures. During the post-partum period, another pregnancy must be avoided by good compliance with a reliable contraceptive method. As for the preventive treatment of mother-to-child HIV transmission, at the moment only AZT can be considered, but its effectiveness remains to be evaluated in therapeutic trials.
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PMID:[Pregnancy in HIV infected women. Current therapeutic indications]. 153 74

The replication cycle of human immunodeficiency virus type 1 (HIV-1) consists of four distinct stages, each of which can be targeted for specific antiviral chemotherapy. The stages are (1) the attachment of virus to the CD4 receptor at the cell surface; (2) the uncoating of viral nucleic acid and its conversion via viral reverse transcriptase activity to DNA; (3) cellular multiplication, accompanied by the replication of integrated proviral DNA and production of viral RNA and proteins; and (4) the assembly and liberation of progeny virus from the cell and the potential reinitiation of the replication cycle in previously uninfected cells. Since each of these steps represents a potential target for anti-HIV chemotherapy, it is apparent that the rationale for the use of antiviral drugs is not dissimilar from the manner in which antineoplastic agents are targeted to specific stages in the replication cycle of tumor cells. As in the case of anticancer chemotherapy, it is hoped that combinations of drugs, which act against different steps in the viral replication cycle, might have synergistic potential. AZT or zidovudine is the most widely used drug to date to impede the replication of HIV-1; it is significant that this compound was designed initially with anticancer chemotherapy in mind. Although AZT therapy has been reasonably successful, this drug has had important toxic side effects. As in the case of many cancer chemotherapeutic agents, drug resistance to AZT is likely to be an important problem, and there have been several reports of the isolation of drug-resistant variants of HIV-1.
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PMID:Strategies in the treatment of AIDS and related diseases: the lessons of cancer chemotherapy. 155 Oct 24

Zidovudine (AZT) inhibits HIV-1 replication in AIDS. A limiting side effect is AZT-induced toxic myopathy. Molecular changes in a rat model of AZT-induced toxic myopathy in vivo helped define pathogenetic molecular, biochemical, and ultrastructural toxic events in skeletal muscle and supported clinical and in vitro findings. After 35 d of AZT treatment, selective changes in rat striated muscle were localized ultrastructurally to mitochondria, and included swelling, cristae disruption, and myelin figures. Decreased muscle mitochondrial (mt) DNA, mtRNA, and decreased mitochondrial polypeptide synthesis in vitro were found in parallel. Mitochondrial molecular changes occurred in absence of altered abundance of cytosolic glyceraldehyde-3-phosphate dehydrogenase, or sarcomeric mitochondrial creatine kinase mRNAs. Quadriceps mitochondrial DNA polymerase gamma activity was similar in both AZT-treated and control rats. In vivo findings with rats support the hypothesis that AZT-induced inhibition of mtDNA replication has an effect of depressing the abundance of striated muscle mtDNA, mtRNA, and mitochondrial polypeptide synthesis. This experimental approach may be useful to examine mitochondrial or toxic myopathies.
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PMID:Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria. 155 93


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