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Biomedical subjects

R Yarchoan

Publications and source records attributed to R Yarchoan.

At least 37 records · Page 2Linked to original sources
PubMed2000

Systemic chemotherapy for HIV-associated lymphoma in the era of highly active antiretroviral therapy.

Treatment of AIDS-associated non-Hodgkin lymphoma poses a complex and multifaceted challenge for the physician. Treatment responses to cytotoxic chemotherapy are relatively poor, relapse rates are high, and AIDS progression continues to be a major concern in patients receiving dose-intensive antilymphoma therapy. The recent advances in anti-HIV therapy have not seen a clear counterpart in improved antilymphoma therapy, but trials are underway that may help move this field forward. For patients who achieve a complete and durable response to antilymphoma therapy, potent antiretroviral therapy may help improve the prognosis from AIDS progression. Major questions persist, however, on the role of chemotherapy dose intensity, the best use of antiretroviral therapy during the administration of lymphoma therapy, and the optimal design of studies that can address these questions.

Anti-HIV Agents↗
PubMed2000

Activity of thalidomide in AIDS-related Kaposi's sarcoma.

PURPOSE: To assess the toxicity and activity of oral thalidomide in Kaposi's sarcoma (KS) in a phase II dose-escalation study. PATIENTS AND METHODS: Human immunodeficiency virus (HIV)-seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed. RESULTS: Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm(3) (range, 14 to 646 cells/mm(3)) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months. CONCLUSION: Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1999

HIV-specific immunity following immunization with HIV synthetic envelope peptides in asymptomatic HIV-infected patients.

OBJECTIVE: A phase I trial was conducted to evaluate the safety and immunogenicity of an HIV synthetic peptide vaccine in HIV-seropositive individuals. The immunogens used in this study were PCLUS 3-18MN and PCLUS 6.1-18MN envelope peptides. METHODS: Eight HIV-infected patients received six subcutaneous injections of 160 microg PCLUS 3-18MN in Montanide ISA 51 and were followed longitudinally for a year after the first immunization. Peripheral blood mononuclear cells (PBMC) were tested for peptide-specific T helper and cytotoxic T cell (CTL) responses, HIV-1MN neutralizing antibodies and antibodies against HIV PCLUS 3 and P18 MN peptides. RESULTS: PCLUS 3-1 8MN-specific T helper responses were significantly increased at 36 weeks (P < 0.05, after adjustment for multiple comparisons) following initial immunization with PCLUS 3-18MN. A P18MN-specific CTL response, not present prior to vaccination, was observed after immunization in one patient. Serum HIV-1 MN-neutralizing antibody titers increased in each of the three patients who had low titers prior to immunization. Plasma HIV RNA levels and CD4 cell counts did not change appreciably during the study period. CONCLUSIONS: This trial demonstrates that both peptides can be safely administered to HIV-infected individuals and that PCLUS 3-18MN induces increases in HIV peptide-specific immune responses.

AIDS Vaccines↗
PubMed1999

Involvement of interleukin-10 (IL-10) and viral IL-6 in the spontaneous growth of Kaposi's sarcoma herpesvirus-associated infected primary effusion lymphoma cells.

Primary effusion lymphoma (PEL) is a distinct type of lymphoma associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. To determine the factors responsible for the unrestrained proliferation of PEL, we have studied the growth factor requirements of the PEL-derived BCBL-1 and BC-1 cell lines. Both cell lines were found to be autocrine growth factor dependent and to release human interleukin-6 (IL-6), viral IL-6 (vIL-6), and human IL-10 in the culture supernatant. To establish whether these cytokines contribute to autocrine growth, neutralizing antibodies against human IL-6, vIL-6, human IL-10, and soluble IL-10 receptor were used. These experiments showed that human IL-10 and, to a lesser degree, vIL-6 serve as autocrine growth factors for BCBL-1 and BC-1 cells. Thus, human IL-10 and vIL-6 are growth factors released and used by PEL cells for autonomous proliferation and may be critical to the development and progression of PEL.

Antibodies, Monoclonal↗
PubMed1999

Therapy for Kaposi's sarcoma: recent advances and experimental approaches.

The past several years have seen demonstrable progress in the therapy of Kaposi's sarcoma (KS). Liposomal anthracyclines and paclitaxel have been found to be highly effective chemotherapeutic agents for this disease. Recent advances in our understanding of the pathogenesis of KS have led to the consideration of various new experimental agents. Two antiangiogenesis agents, TNP-470 and thalidomide, have been determined to induce some responses in KS, and others are now in early clinical trials or in preclinical development. Oral 9-cis retinoic acid has been shown to have anti-KS activity, and preliminary studies suggest that a urinary protein found in preparations of human chorionic gonadotropin also has activity. Effective anti-HIV treatment has been shown to affect the growth of KS, and the discovery of a new herpesvirus as a causative agent for KS has offered new potential targets for attack.

Administration, Oral↗
PubMed1999

Reactivation and persistence of human herpesvirus-8 infection in B cells and monocytes by Th-1 cytokines increased in Kaposi's sarcoma.

Patients with Kaposi's sarcoma (KS) have a human herpesvirus-8 (HHV-8) load higher than patients without KS and present a CD8(+) T-cell activation with production of Th1-type cytokines both in tissues and peripheral blood mononuclear cells (PBMC). Because in tissues of KS patients detection of inflammatory cytokines (IC) can precede detection of HHV-8 DNA and because signs of immunoactivation and/or dysregulation can precede KS development, we investigated the effect of IC on HHV-8 infection. To achieve this goal, PBMC and purified cell populations from 45 patients with KS and 45 patients at risk of KS were analyzed for HHV-8 DNA and/or gene expression and for cell survival, growth, and phenotype before or after culture with or without the IC increased in KS. The results indicate that PBMC that are polymerase chain reaction (PCR)-positive at day 0 generally loose the virus upon culture. However, the presence of IC maintains HHV-8 DNA load in cultured cells. In addition, IC increase viral load to detectable levels in PBMC from serologically positive patients that were PCR-negative before culture. gamma Interferon is sufficient for these effects, whereas tumor necrosis factor and interleukin-6 have little or no activity. The increase of HHV-8 DNA by IC is observed after short-term (7 days) or long-term (28 days) culture of the cells and occurs in one or both of the two circulating cell types that are infected in vivo: B cells and monocytes. In both cases it is associated with lytic gene expression, suggesting that virus reactivation is one of the most likely mechanisms for the effect of IC on virus load. However, IC have also effects on the cells target of HHV-8 infection, because they increase B-cell survival and induce the growth and differentiation of monocytes into KS-like spindle cells with markers of endothelial macrophages. Because cells with markers of endothelial macrophages are present in blood and lesions from KS patients and are infected by HHV-8, these data may explain the high HHV-8 load associated with KS development and suggest that infected monocytes may carry the virus to tissues, transmit the infection, or differentiate in loco in spindle cells with endothelial macrophage markers.

Acquired Immunodeficiency Syndrome↗
PubMed1999

A phase I trial of the pharmacokinetics, toxicity, and activity of KNI-272, an inhibitor of HIV-1 protease, in patients with AIDS or symptomatic HIV infection.

The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase I trial. After an initial phase in which the pharmacokinetics were assessed, 37 patients with AIDS or symptomatic HIV infection and 100-400 CD4 cells/mm3 were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not appreciably different in the fasting and post-prandial state. The dose limiting toxicity was hepatic transaminase elevation; this could be reduced by escalating the dose over 4 weeks. When administered this way, the maximum tolerated oral dose was 40 mg/kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2-0.3 log10 copies/ml plasma HIV RNA; these decreases persisted through 7-8 weeks of treatment. There was an upward trend in the CD4 count at the 40 mg/kg per day dose but not at other doses. Additional studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Conserved cysteines of the human immunodeficiency virus type 1 protease are involved in regulation of polyprotein processing and viral maturation of immature virions.

We investigated the role of the two highly conserved cysteine residues, cysteines 67 and 95, of the human immunodeficiency virus type 1 (HIV-1) protease in regulating the activity of that protease during viral maturation. To this end, we generated four HIV-1 molecular clones: the wild type, containing both cysteine residues; a protease mutant in which the cysteine at position 67 was replaced by an alanine (C67A); a C95A protease mutant; and a double mutant (C67A C95A). When immature virions were produced in the presence of an HIV-1 protease inhibitor, KNI-272, and the inhibitor was later removed, limited polyprotein processing was observed for wild-type virion preparations over a 20-h period. Treatment of immature wild-type virions with the reducing agent dithiothreitol considerably improved the rate and extent of Gag processing, suggesting that the protease is, in part, reversibly inactivated by oxidation of the cysteine residues. In support of this, C67A C95A virions processed Gag up to fivefold faster than wild-type virions in the absence of a reducing agent. Furthermore, oxidizing agents, such as H2O2 and diamide, inhibited Gag processing of wild-type virions, and this effect was dependent on the presence of cysteine 95. Electron microscopy revealed that a greater percentage of double-mutant virions than wild-type virions developed a mature-like morphology on removal of the inhibitor. These studies provide evidence that under normal culture conditions the cysteines of the HIV-1 protease are susceptible to oxidation during viral maturation, thus preventing immature virions from undergoing complete processing following their release. This is consistent with the cysteines being involved in the regulation of viral maturation in cells under oxidative stress.

Alanine↗
PubMed1998

Pilot study of the immunologic effects of recombinant human growth hormone and recombinant insulin-like growth factor in HIV-infected patients.

OBJECTIVE: To study the immunologic effects of recombinant human growth hormone (rhGH), recombinant human insulin-like growth factor type 1 (rhIGF-1), or the combination, in patients with moderately advanced HIV infection. DESIGN: Randomized but not blinded trial. SETTING: Government medical research center. PATIENTS: Twenty-four HIV-infected patients with CD4 cell counts of 100-400 x 10(6)/l who were receiving nucleoside antiretroviral therapy. INTERVENTIONS: Either rhGH, rhIGF-1, or the combination was administered subcutaneously for 12 weeks. MAIN OUTCOME MEASURES: Immunologic parameters, including T-cell subsets and assays of in vitro interleukin (IL)-2 production in response to antigens and mitogens, and safety profile. RESULTS: Plasma IGF-1 levels were low or low-normal prior to treatment and increased with all three therapies. There were no significant changes in CD4 cell counts, RA/RO CD4 cell subsets, natural killer cell function, immunoglobulin levels, or in vitro IL-2 production in response to mitogen or alloantigens. However, there was an upward trend (and for p18IIIB a statistically significant increase) in the in vitro IL-2 production in response to each of five HIV envelope peptides. Potential toxic effects included fatigue, arthralgia, edema, myalgia, and headache. Patients also were noted to have weight gain averaging 4 kg early in the course of treatment. CONCLUSIONS: These results suggest that treatment with rhGH/rhIGF-1 was reasonably well tolerated and that modest improvement in HIV-specific immune function was attained. Further studies will help clarify the therapeutic potential of rhGH/rhIGF-1 as an immunostimulator in the setting of HIV infection.

Adult↗
PubMed1998

Glycocalicin levels in the plasma of HIV+ patients: an indicator of platelet turnover.

Glycocalicin (GC) is the carbohydrate-rich portion of platelet membrane glycoprotein Ib(alpha) that can be cleaved from circulating platelets by proteases. The plasma GC level is an indicator of platelet turnover. Using an ELISA for GC, we assayed the plasma of 20 normal children (age 6 to 13 years), 50 HIV+ children (ages 4 to 18 years), 32 normal adults (ages 21 to 53 years), and 50 HIV+ adults (ages 24 to 66 years). The results were adjusted for individual platelet counts to give GC indexes (GCI). The normal children and the normal adults had significantly different GCI distributions (P = .002). In both normal and HIV+ individuals the GCI decreased with increasing platelet count (-.73 < r < -.34). Twenty-eight percent of the HIV+ children and 28% of the HIV+ adults had elevated GCI values. The majority of these elevated values occurred in patients with platelet counts >100,000/microL. Neither the GCI nor the platelet count was correlated with viral load. The platelet count, however, was weakly correlated with the CD4 count in both children (r = .31) and adults (r = .30) infected with HIV. Also, the CD4 count was weakly and inversely correlated with GCI in HIV+ adults (r = -.34) and in children (r = -.24). We conclude that increased GCI and, by implication, increased platelet turnover is a relatively common feature of advanced HIV disease. Furthermore, GCI may be elevated in HIV+ patients even with a platelet count >100,000/microL, suggesting increased platelet turnover before thrombocytopenia develops.

Adolescent↗
PubMed1998

Emergence of multi-dideoxynucleoside-resistant human immunodeficiency virus type 1 variants, viral sequence variation, and disease progression in patients receiving antiretroviral chemotherapy.

A set of five reverse transcriptase mutations, which include Q151M, is known to confer multi-dideoxynucleoside resistance (MDR) in human immunodeficiency virus type 1 (HIV-1). MDR mutations were found in 6 (17%) HIV-1 isolates from 36 patients, most of whom were receiving long-term combination therapy. Q151M was among the first of the substitutions to appear. Additional substitutions were observed, although none were common among all 6 patients. Certain zidovudine-related mutations were not observed together with the MDR mutations, indicating possible enzymatic constraint. During chemotherapy, the HIV-1 RNA levels in the 6 patients initially decreased and then rose. Initially, CD4 cell counts also responded favorably but were near or below baseline beyond 40 months of therapy. Such loss of clinical benefits appeared to coincide with the appearance of the MDR mutations. A common background genotype was not observed among HIV-1 isolates with or without MDR.

Adult↗
PubMed1998

Relative potency of protease inhibitors in monocytes/macrophages acutely and chronically infected with human immunodeficiency virus.

The activity of three human immunodeficiency virus (HIV) protease inhibitors was investigated in human primary monocytes/macrophages (M/M) chronically infected by HIV-1. Saquinavir, KNI-272, and ritonavir inhibited the replication of HIV-1 in vitro, with EC50s of approximately 0.5-3.3 microM. However, only partial inhibition was achievable, even at the highest concentrations tested. Also, the activity of these drugs in chronically infected M/M was approximately 7- to 26-fold lower than in acutely infected M/M and approximately 2- to 10-fold lower than in chronically infected H9 lymphocytes. When protease inhibitors were removed from cultures of chronically infected M/M, production of virus rapidly returned to the levels found in untreated M/M. Therefore, relatively high concentrations of protease inhibitors are required to suppress HIV-1 production in chronically infected macrophages, and such cells may be a vulnerable point for the escape of virus in patients taking these drugs.

Anti-HIV Agents↗
PubMed1998

Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi's sarcoma.

PURPOSE: To investigate the antitumor activity and safety of paclitaxel in patients with advanced human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS). PATIENTS AND METHODS: Twenty-nine patients with advanced HIV-associated KS were enrolled. The patients were overall quite immunosuppressed (median CD4 count, 15 cells/microL). Paclitaxel was initially administered at 135 mg/m2 over 3 hours every 3 weeks without filgrastim support; the dose was increased as tolerated to a maximum of 175 mg/m2. Patients who failed to respond or progressed could then receive filgrastim support or paclitaxel administered over 96 hours. RESULTS: Of 28 assessable patients, 20 had major responses (18 partial responses [PRs], one clinical complete response [CR], and one CR), for a major response rate of 71.4% (95% confidence interval [CI], 51.3% to 86.8%). Each of the five patients with pulmonary KS responded, as did all four assessable patients who had previously received anthracycline therapy for KS. Of six patients who went on to receive a 96-hour infusion of paclitaxel, five had major responses. Neutropenia was the most frequent dose-limiting toxicity; possible novel toxicities included late fevers, late rash, and eosinophilia. Two patients developed an elevated creatinine concentration and one cardiomyopathy. CONCLUSION: Paclitaxel has substantial activity against advanced HIV-associated KS as a single agent, even in patients with pulmonary involvement or who had previously received anthracyclines. Further research is needed to define the optimal treatment schedule and its role vis-a-vis the other available therapies for this disease.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Human herpesvirus 8 (HHV-8) in the pathogenesis of Kaposi's sarcoma and other diseases.

The discovery of Kaposi's Sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/ HHV-8) and subsequent studies of this virus have provided a body of evidence that support the concept that this is an etiologic agent for Kaposi's sarcoma (KS). Several studies have indicated that this virus may also be a causal agent for primary effusion lymphoma (PEL) and Castleman's disease as well. First generation serologic assays for HHV-8 have now been developed. The preponderance of data suggest that the incidence of HHV-8 infection is highest in populations at risk for KS: male homosexuals, immunosuppressed patients, and those who live in endemic regions. HHV-8 encodes for functional homologs of human proteins that may play a role in the development of disease. As we learn more about the steps by which this virus can lead to KS and/or other diseases, rational therapies and preventative strategies may be possible.

Castleman Disease↗