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Biomedical subjects

Alexandra M Levine

Publications and source records attributed to Alexandra M Levine.

At least 55 records · Page 3Linked to original sources
PubMed2004

Treatment of AIDS related non-Hodgkin's lymphoma with combination mitoguazone dihydrochloride and low dose CHOP chemotherapy: results of a phase II study.

PURPOSE: To evaluate the response and side effects of combination therapy with low dose CHOP chemotherapy and mitoguazone dihydrochloride in patients with non-Hodgkin's lymphoma associated with the acquired immunodeficiency syndrome (AIDS-NHL). METHODS: Eighteen patients newly diagnosed with intermediate or high-grade AIDS-NHL were treated with low dose CHOP as follows: day 1, cyclophosphamide 350 mg/m(2), intravenously (IV); doxorubicin 25mg/m(2) IV; vincristine 2mg IV; and prednisone 100mg given orally on days 1 through 5. In addition, mitoguazone dihydrochloride was given at a dose of 600 mg/m(2) IV on days 1 and 15 of each 28-day treatment cycle. RESULTS: Seventeen males and one female patient were accrued. Twelve patients had high-grade pathologies while the remainder had an intermediate grade pathology (diffuse large cell). The median CD4+ lymphocyte count was 98/dl (range 1-924). Three patients (17%) reported an AIDS-defining illness prior to lymphoma diagnosis. Of 14 evaluable patients, 6 (43%) achieved a complete remission and 5 (35%) a partial remission. The median failure free and overall survival times were 6.5 and 8.4 months, respectively. Major toxicity was hematologic with grade 3 or 4 neutropenia in 72%; two patients died of neutropenic sepsis. CONCLUSIONS: Mitoguazone in combination with low dose CHOP is a safe regimen, associated with a response rate of 79% (CR 43%, PR 36%, 95% CI=49-95%). These preliminary results suggest no major improvement in terms of response over use of CHOP without mitoguazone.

Adult↗
PubMed2004

Making dendritic cells from the inside out: lentiviral vector-mediated gene delivery of granulocyte-macrophage colony-stimulating factor and interleukin 4 into CD14+ monocytes generates dendritic cells in vitro.

We have evaluated a one-hit lentiviral transduction approach to genetically modifying monocytes in order to promote autocrine and paracrine production of factors required for their differentiation into immature dendritic cells (DCs). High-titer third-generation self-inactivating lentiviral vectors expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) efficiently achieved simultaneous and persistent codelivery of the transgenes into purified human CD14+ monocytes. Coexpression of GM-CSF and IL-4 in CD14+ cells was sufficient to induce their differentiation into a DC-like phenotype, as evidenced by their morphology, immature immunophenotypic profile (CD14-, CD1a+, CD80+, CD86+, MHC-I+, MHC-II+), and their ability to further develop into a mature phenotype (CD83+) on further treatment with soluble CD40 ligand. Mixed lymphocyte reactions showed that the T cell-stimulating activity of lentivirus-modified DCs was superior to that of DCs grown by conventional methods. Lentivirus-modified DCs displayed efficient antigen-specific, MHC class I-restricted stimulation of autologous CD8+ T cells, as shown by IFN-gamma production and CTL assays. DCs coexpressing GM-CSF and IL-4 could be kept metabolically active and viable in culture for 14 days in the absence of exogenously added growth factors, unlike conventionally produced DCs. Coexpression of FLT3 ligand did not improve the viability, expansion, or immunologic performance of lentivirus-modified DCs. This article demonstrates the proof-of-concept to genetically convert monocytes to DC-type antigen-presenting cells with lentiviral vectors.

Analysis of Variance↗
PubMed2004

HPV testing for triage of HIV-infected women with papanicolaou smears read as atypical squamous cells of uncertain significance.

PURPOSE: To assess the utility of testing for high-risk human papillomavirus (HPV) DNA as a triage strategy for detecting cervical intraepithelial neoplasia (CIN) grade 2/3 in women with human immunodeficiency virus-1 (HIV-1) infection and cytology read as atypical cells of uncertain significance (ASCUS). METHODS: Conventional cervical cytology and cervicovaginal lavage were obtained at 6-month intervals between October 1, 1994, and September 30, 2002, from women enrolled in the Women's Interagency HIV Study, a multicenter cohort studying the natural history of HIV in women. HPV typing was performed by PCR. HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 were classified as carrying high oncogenic risk. Women with ASCUS smears were referred for colposcopy. Analyses of the sensitivity of HPV testing were cross-sectional, using colposcopy results within 90 days of first ASCUS result. RESULTS: Of the 270 women evaluated, 7 (3%) had CIN 2, and 3 (1%) had CIN3 or adenocarcinoma in situ. High-risk HPV DNA was found in 81 (30%) of the 270 participants. The sensitivity of high-risk HPV DNA detection for CIN 2/3 was 50% (95% CI 0.19, 0.81), the specificity was 71% (95% CI 0.65, 0.76), the positive predictive value was 6% (95% CI 0.01, 0.11), and the negative predictive value was 97% (95% CI 0.95, 1.00). HPV of any risk type was found in 176 (65%) of the 270 women, including 9 of 10 women with CIN 2/3, for a sensitivity of 90% (95% CI 0.56, 1.00), a specificity of 36% (95% CI 0.30, 0.42), a positive predictive value of 5% (95% CI 0.02, 0.08), and a negative predictive value of 99% (95% CI 0.94, 1.00). CONCLUSIONS: For women with HIV and Papanicolaou smears read as ASCUS, DNA testing for high risk HPV may not be sensitive enough for clinical use.

Adult↗
PubMed2004

Once-weekly epoetin alfa improves quality of life and increases hemoglobin in anemic HIV+ patients.

This prospective, open-label, multicenter trial evaluated the effects of once-weekly (qw) epoetin alfa on quality of life (QOL) and hemoglobin (Hb) levels in anemic human immunodeficiency virus (HIV)-infected adult receiving antiretroviral therapy. A total of 650 patients with Hb < or = 11 g/dl received epoetin alfa 40,000 U qw subcutaneously, with dose escalation to 60,000 qw if Hb increase was <1 g/dl after 4 weeks. The linear Analog Scale Assessment (LASA) overall QOL score, LASA energy score, and LASA activity score each significantly improved from baseline to final measurement (p < 0.0001 for each parameter). Improvements in the Medical Outcomes Study (MOS)-HIV physical and mental health summary scores were also significant (p < 0.0001), and coincided with Hb increases. Mean Hb increased from baseline to final measurement by 2.5 g/dl (95% CI: 2.3, 2.6 g/dl; p < 0.0001). Objective hematological response rate, defined as a > or = 1 g/dl Hb increase from baseline to week 8, was 86%. Hemoglobin increased significantly in all subgroups of race, zidovudine use, CD4+ cell count, and viral load. Once-weekly epoetin alfa was well tolerated. Once-weekly epoetin alfa is effective in improving QOL and Hb measures.

Adult↗
PubMed2004

Hepatitis C virus infection activates the immunologic (type II) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes.

Hepatitis C virus (HCV) infection causes hepatitis, hepatocellular carcinoma, and B-cell lymphomas in a significant number of patients. Previously we have shown that HCV infection causes double-stranded DNA breaks and enhances the mutation frequency of cellular genes, including proto-oncogenes and immunoglobulin genes. To determine the mechanisms, we studied in vitro HCV infection of cell culture. Here we report that HCV infection activated the immunologic (type II) isoform of nitric oxide (NO) synthase (NOS), i.e., inducible NOS (iNOS), thereby inducing NO, which in turn induced DNA breaks and enhanced the mutation frequencies of cellular genes. Treatment of HCV-infected cells with NOS inhibitors or small interfering RNA specific for iNOS abolished most of these effects. Expression of the core protein or nonstructural protein 3 (NS3), but not the other viral proteins, in B cells or hepatocytes induced iNOS and DNA breaks, which could be blocked by NOS inhibitors. The core protein also enhanced the mutation frequency of cellular genes in hepatocytes derived from HCV core transgenic mice compared with that in control mice. The iNOS promoter was activated more than fivefold in HCV-infected cells, as revealed by a luciferase reporter assay driven by the iNOS promoter. Similarly, the core and NS3 proteins also induced the same effects. Therefore, we conclude that HCV infection can stimulate the production of NO through activation of the gene for iNOS by the viral core and NS3 proteins. NO causes DNA breaks and enhances DNA mutation. This sequence of events provides a mechanism for HCV pathogenesis and oncogenesis.

Animals↗
PubMed2004

Medically eligible women who do not use HAART: the importance of abuse, drug use, and race.

OBJECTIVES: We investigated the prevalence and characteristics of HIV-positive women who do not report highly active antiretroviral therapy (HAART) use. METHODS: We analyzed HAART use among 1165 HIV-positive participants in the Women's Interagency HIV Study. RESULTS: Between October 1, 2000, and March 31, 2001, 254 women with clinical indications for HAART reported not using it, 635 reported HAART use, and 276 had no clinical indications. In multivariate analysis, using crack/cocaine/heroin and a history of abuse decreased the likelihood of using HAART, whereas being White increased it. CONCLUSIONS: One of 4 women for whom HAART was indicated reported not using HAART. Childhood sexual abuse prevention, more intensive abuse treatment, and continuing drug treatment may enhance HIV disease treatment of women.

Adult↗
PubMed2003

Human papillomavirus type 16 and immune status in human immunodeficiency virus-seropositive women.

BACKGROUND: Human papillomavirus (HPV) type 16 is etiologically associated with approximately half of all cervical cancers. It is important, therefore, to determine the characteristics that distinguish HPV16 from other HPV types. A preliminary result based on cross-sectional baseline data in the Women's Interagency Human Immunodeficiency Virus (HIV) Study (WIHS) suggested that the prevalence of HPV16 might have a weaker association with immune status in HIV-seropositive women than that of other HPV types. To address this issue, we examined HPV test results from repeated study visits in the WIHS and from an independent study, the HIV Epidemiology Research Study (HERS). METHODS: HIV-seropositive women in the WIHS (n = 2058) and in the HERS (n = 871) were assessed semiannually. HPV DNA was detected in cervicovaginal lavage specimens by using polymerase chain reaction assays. Prevalence ratios were used to compare the prevalence of each HPV type in women with the lowest CD4+ T-cell counts (<200 T cells/mm3) with that of women with the highest CD4+ T-cell counts (> or =500 T cells/mm3). A summary prevalence ratio for each HPV type (i.e., across visits and studies) was estimated using generalized estimating equations. The association of CD4+ T-cell stratum with type-specific HPV incidence was measured using multivariable Cox regression models. All statistical tests were two-sided. RESULTS: The prevalence ratio for HPV16 was low compared with that of other HPV types at every study visit in both cohorts. The generalized estimating equation summary prevalence ratio for HPV16 (1.25, 95% confidence interval [CI] = 0.97 to 1.62) was the smallest measured, and it was statistically significantly lower than that of all other HPV types combined (P =.01). The association of CD4+ T-cell stratum with HPV16 incidence was also among the smallest measured (hazard ratio = 1.69, 95% CI = 1.01 to 2.81). CONCLUSIONS: The prevalent and incident detection of HPV16 is more weakly associated with immune status in HIV-seropositive women than that of other HPV types, suggesting that HPV16 may be better at avoiding the effects of immune surveillance, which could contribute to HPV16's strong association with cervical cancer.

AIDS-Related Opportunistic Infections↗
PubMed2003

Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias.

PURPOSE: Troxacitabine has significant single-agent activity. This study was conducted to define the dose-limiting toxicities (DLTs) of its combination with cytarabine (ara-C), idarubicin, or topotecan. PATIENTS AND METHODS: Patients with refractory acute myeloid leukemia (AML), advanced myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were initially randomly assigned to receive troxacitabine 5.0 mg/m(2) by intravenous (IV) infusion over 30 minutes on days 1 to 5 with ara-C 1.0 g/m(2)/d IV [DOSAGE ERROR CORRECTED] over 2 hours on days 1 to 5, idarubicin 12 mg/m(2) by 5 minute IV infusion on days 1 to 3, or topotecan 1.0 mg/m(2) as an continuous IV infusion on days 1 to 5. Doses were then adjusted to define DLT for each combination. RESULTS: Eighty-seven patients (68 AML, eight MDS, 11 CML-BP) were treated. DLTs were hepatic transaminitis, hyperbilirubinemia, and hand foot syndrome (HFS) on the troxacitabine plus ara-C combination. The recommended phase II doses were 6 mg/m(2) once a day for 5 days and 1.0g/m(2) once a day for 5 days, respectively. DLTs were diarrhea, rash, and mucositis on the troxacitabine plus topotecan combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 0.75 mg/m(2) once a day for 5 days, respectively. DLTs were HFS, rash, and mucositis on the troxacitabine plus idarubicin combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 9 mg/m(2) once a day for 3 days, respectively. Among 74 evaluable patients with AML or MDS, 10 (13%) achieved complete remission and four (5%) had hematologic improvement. Two of 11 (18%) evaluable patients with CML-BP returned to chronic phase. CONCLUSION: Troxacitabine-based combinations had significant antileukemic activity.

Adolescent↗
PubMed2003

Anemia in the setting of cancer and human immunodeficiency virus.

Anemia commonly occurs in patients with cancer or human immunodeficiency virus (HIV) infection as a result of the disease, its treatment, or both. The negative impact of anemia on patient quality of life (QOL), functional status, and treatment outcomes underscores the need for its correction in these patients. In anemic patients with cancer or HIV infection, treatment with epoetin alfa increases hemoglobin (Hb) levels, decreases transfusion requirements, and improves QOL. In both settings, the gains in overall QOL have been significantly and directly related to increases in Hb, with maximum QOL gains in the range of Hb levels of 11-13 g/dL, supporting the need to achieve and maintain Hb levels > or =12 g/dL in an effort to preserve and maximize QOL benefits. A potential survival benefit has also been associated with correction of anemia in patients with HIV infection--and possibly in those with cancer as well.

Anemia↗
PubMed2003

Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptotic effects of virus infection.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Studies of HCV replication and pathogenesis have so far been hampered by the lack of an efficient tissue culture system for propagating HCV in vitro. Although HCV is primarily a hepatotropic virus, an increasing body of evidence suggests that HCV also replicates in extrahepatic tissues in natural infection. In this study, we established a B-cell line (SB) from an HCV-infected non-Hodgkin's B-cell lymphoma. HCV RNA and proteins were detectable by RNase protection assay and immunoblotting. The cell line continuously produces infectious HCV virions in culture. The virus particles produced from the culture had a buoyant density of 1.13 to 1.15 g/ml in sucrose and could infect primary human hepatocytes, peripheral blood mononuclear cells (PBMCs), and an established B-cell line (Raji cells) in vitro. The virus from SB cells belongs to genotype 2b. Single-stranded conformational polymorphism and sequence analysis of the viral RNA quasispecies indicated that the virus present in SB cells most likely originated from the patient's spleen and had an HCV RNA quasispecies pattern distinct from that in the serum. The virus production from the infected primary hepatocytes showed cyclic variations. In addition, we have succeeded in establishing several Epstein-Barr virus-immortalized B-cell lines from PBMCs of HCV-positive patients. Two of these cell lines are positive for HCV RNA as detected by reverse transcriptase PCR and for the nonstructural protein NS3 by immunofluorescence staining. These observations unequivocally establish that HCV infects B cells in vivo and in vitro. HCV-infected cell lines show significantly enhanced apoptosis. These B-cell lines provide a reproducible cell culture system for studying the complete replication cycle and biology of HCV infections.

Amino Acid Sequence↗
PubMed2003

Human immunodeficiency virus hematology.

The advent of potent antiretroviral therapy has altered the expected natural history of human immunodeficiency virus (HIV) infection and of many previously associated opportunistic complications, including malignancies. At the same time, HIV suppression has not affected all of these complications equally and the longer expected survival of infected patients may allow the development of newer complications. Additionally, the use of potent antiretroviral combination therapy may itself lead to hematological toxicities. Together these changes affect the consultation role of the hematology-oncology specialist in comprehensive HIV care and demand ongoing education. In Section I, Dr. Paul Volberding reviews the biology of antiretroviral drug development and the progression in discovering new agents as the viral life cycle is further elucidated. He briefly summarizes the process of combining agents to achieve the degree of viral suppression required for long-term clinical benefit. In Section II, Dr. Kelty Baker reviews the effects of HIV and its therapy on hematologic dyscrasia and clotting disorders. She summarizes how therapy may decrease certain previously common manifestations of HIV disease while adding new problems likely to result in referral to the hematologist. In addition, she addresses the role of secondary infections, such as parvovirus, in this spectrum of disorders. In Section III, Dr. Alexandra Levine discusses the still challenging aspects of HIV associated non-Hodgkin's lymphoma and the association between HIV infection and Hodgkin's disease. She addresses current controversies in the pathogenesis of HIV related lymphomas and summarizes a number of recent trials of combination chemotherapy, with or without monoclonal antibodies, in their management. Additionally, she reviews the complex relationship of HIV disease with multicentric Castleman's disease and recent attempts to manage this disorder.

Anti-Retroviral Agents↗
PubMed2002

Characteristics of indolent non-Hodgkin lymphoma in patients with type 1 human immunodeficiency virus infection.

BACKGROUND: There is recent evidence that the incidence of indolent non-Hodgkin lymphoma (NHL) appears to be increased in persons with the acquired immunodeficiency syndrome (AIDS). The current study was conducted to describe the clinical, immunologic, and pathologic characteristics of indolent B-cell lymphoma in patients infected with the human immunodeficiency virus (HIV). METHODS: The current report was a retrospective study of 10 cases of indolent NHL identified from the AIDS-Lymphoma Registry at the University of Southern California School of Medicine. These patients were compared with 336 consecutive patients with systemic intermediate/high-grade AIDS-related NHL who were diagnosed and treated at a single institution. RESULTS: The pathology of the indolent cases included follicular lymphoma (five patients), small lymphocytic lymphoma (two patients), and one case each of mucosa-associated lymphoid tissue (MALT), monocytoid B-cell, and marginal zone lymphoma. When comparing the indolent lymphomas with the intermediate/high-grade AIDS-NHL cases, no differences were observed with regard to demographic characteristics or history of prior opportunistic infection. HIV patients with indolent lymphomas were found to have a significantly higher median CD4+ lymphocyte count compared with patients with intermediate/high-grade NHL (531 /mm3 vs. 90 /mm3) (P < 0.0001). Bone marrow involvement was significantly more common in indolent NHL cases (50%) versus intermediate/high-grade NHL cases (17%) (P = 0.02). The median survival for patients with indolent NHL was significantly longer compared with patients with intermediate/high-grade NHL (66.8 months vs. 7.1 months) (P = 0.007). CONCLUSIONS: Indolent lymphomas occurring in patients infected with HIV appear to differ from intermediate/high-grade lymphomas with regard to immune status and propensity for bone marrow involvement and prolonged survival. The median survival in the group of HIV-seropositive patients with indolent NHL examined in the current study was found to be comparable to that reported in HIV-negative individuals.

Adult↗
PubMed2002

Evaluation and management of HIV-infected women.

The rate of newly diagnosed AIDS in the United States is increasing fastest in women, who are infected with HIV primarily through heterosexual transmission. Approximately 60% of these women are African American, and 18% are Latina. A gynecologic infection is the most common symptom that leads to initial medical evaluation. Specific studies at baseline should include CD4 lymphocyte count, HIV-1 RNA level, and gynecologic examination with Papanicolaou smear. Decisions about initiation of antiretroviral therapy depend on the patient's clinical diagnoses, her willingness to adhere to treatment, and CD4 lymphocyte and HIV-1 RNA levels. Levels of HIV-1 RNA may be somewhat lower in women than in men at the same CD4 count, whereas women have higher CD4 lymphocyte counts at the time of AIDS diagnosis. However, prospective trials have not yet indicated the need to change the threshold CD4 lymphocyte counts or HIV-RNA levels for initiation of therapy in women. The efficacy of antiretroviral therapy appears to be similar in men and women, although women are more likely to experience toxicities. Abnormal Papanicolaou smears occur in approximately 40% of women at baseline, and 58% are infected with human papillomavirus. The prevalence of both conditions increases with lower CD4 lymphocyte counts and higher HIV-1 RNA levels. Precursor lesions to cervical cancer may be effectively treated, but almost 50% recur within 1 year, mandating careful follow-up. Referral should be sought for specialized gynecologic care and for issues related to HIV itself, since survival is prolonged in patients treated by physicians who are experienced in treating HIV. When they are provided the same access to care, HIV-infected women have similar prognoses as HIV-infected men.

Adult↗
PubMed2002

Use of mammographic screening by HIV-infected women in the Women's Interagency HIV Study (WIHS).

BACKGROUND: Although HIV-positive women may be less likely than women in general to receive mammography due to socioeconomic disadvantage, HIV diagnosis may increase opportunities for medical interactions which encourage mammography. METHODS: HIV-positive (2,059) and HIV-negative (569) Women's Interagency HIV Study (WIHS) participants reported ever/never history of mammography at baseline (in 1994, 1995) and, at each 6-month follow-up visit, if they had been screened since their last visit. National Health Interview Survey (NHIS) data for 1994 were used to compare WIHS participants to U.S. women. Factors independently related to mammography were determined using logistic regression for baseline data and proportional hazards for follow-up data. Results were adjusted for age. RESULTS: Among women > or =40, fewer WIHS women, regardless of HIV status, reported screening than U.S. women (67% HIV-positive, 62% HIV-negative, 79% NHIS; P < 0.0001). First-time screening while on study was associated with being HIV-positive [rate ratio (95% confidence interval) = 1.6 (1.1, 2.3)]. Factors independently associated with screening were related to health care access and usage. CONCLUSIONS: WIHS women, a disadvantaged population, reported less mammography than the general population. HIV-positive women reported more screening than HIV-negative women, possibly because of greater opportunity to interact with the health care system.

Adult↗
PubMed2002

Multidrug resistance (MDR-1) expression in AIDS-related lymphomas.

P-glycoprotein is a product of the multidrug resistance (MDR-1) gene. In non-Hodgkin's lymphoma, less than 20% of untreated de novo lymphomas express MDR-1 compared with approximately 50% after failure of chemotherapy. We wished to study the expression of MDR-1 in AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Tissue biopsies from 50 patients with newly diagnosed AIDS-NHL were studied by immunohistochemical analysis using C494, a monoclonal antibody specific for the MDR-1 isoform of P-gp. MDR-1 expression was correlated with patient demographics, lymphoma characteristics, response to chemotherapy, and survival. Forty-six males and four females with a median age of 38 years (range 26-63) were studied. A prior AIDS-defining opportunistic infection was reported in 35 patients (70%). The median CD4+ lymphocyte count was 69/mm(3) (range 0-920). Thirty-two patients (63%) had received prior anti-HIV therapy, including a protease inhibitor in five (10%). Pathologic types consisted of diffuse large cell in 13 (26%), immunoblastic in 13 (26%), small non-cleaved in 22 (44%), and high grade not otherwise specified in two (4%). The majority of patients (76%) had stage III/IV disease. Pre-treatment lymphoma tissues from 33 patients (66%) stained positively for MDR-1. MDR-1 positive patients had a significantly lower complete remission rate compared to MDR-1 negative patients (33 versus 65%, P=0.042). Duration of complete response was significantly longer in MDR-1 negative patients compared with MDR-1 positive patients (not reached versus 9.9 months, P=0.003). Strategies to overcome MDR-1 expression may be important for initial treatment in patients with AIDS-NHL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗