Showing papers by "Thomas C. Merigan published in 1994"

Combination Therapy with Zidovudine and Didanosine Selects for Drug-Resistant Human Immunodeficiency Virus Type 1 Strains with Unique Patterns of pol Gene Mutations

Abstract: Drug resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol mutations of HIV-1 strains from patients treated for 1 year with zidovudine, didanosine (ddI), or zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only zidovudine had HIV-1 strains with phenotypic zidovudine resistance or a zidovudine resistance pol mutation at codon 215 (P = .6). In contrast, a ddI resistance mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P < .001). Two patients receiving combination therapy developed resistance to zidovudine and ddI; they had HIV strains with amino acid mutations at codons 62, 75, 77, 116, and 151. Combination therapy with zidovudine and ddI selects for zidovudine-resistant HIV-1 strains lacking a ddI resistance mutation and for multidrug-resistant strains containing novel pol mutations.

Textbook of AIDS Medicine

Abstract: Part 1 Introduction: history. Part 2 Basic science: the virus and its target cells viral genes and their products natural history of HIV-1 disease immunopathogenesis an immunologist's view of HIV infection. Part 3 Epidemiology: epidemiology of HIV infection in industrialized countries epidemiology of AIDS in developing countries public health issues. Part 4 Clinical: clinical spectrum of AIDS special considerations in women special considerations in children HIV and injecting drug users pneumocystis carinii pneumonia toxoplasmosis in the setting of AIDS typical mycobacteria syphillis bacillary angiomatosis tropical diseases in the HIV-infected traveller cryptosporidium and cryptosporidiosis fungi cytomegalovirus infection in patients with HIV infection herpes simplex and varicella zoster virus infections in HIV-infected individuals progressive multifocal leukoence-phalopathy Kaposi's sarcoma and cloacogenic carcinoma associated with AIDS overview of AIDS-related lymphomas - a paradigm of AIDS malignancies AIDS-associated malignant lymphomas AIDS-related lymphomas - clinical aspects ocular sequelae neurologic complications of HIV infection and AIDS cutaneous signs of HIV infection oral manifestations gastro-intestinal manifestations of HIV disease the pancreas in AIDS the peritoneum and mesentery in AIDS liver disease and AIDS renal disease and AIDS cardiac involvement in the patient with AIDS hematologic consequences of HIV infection endocrine abnormalities associated with immunodeficiency virus infection and AIDS the wasting syndrome in AIDS assays for the diagnosis of HIV infections. Part 5 Control and prevention: preventive vaccines therapeutic HIV vaccines immune-based therapies for HIV-1 infection drug discovery biostatistics and clinical study design biochemical pharmacology of nucleoside analogues active against HIV strategies for antiretroviral therapy in adult HIV disease viral resistance to antiretroviral therapy unproven and unconventional therapies psychotherapy and counselling for HIV-positive individuals hospice care and pain management AIDS in health care workers managing occupational exposures to HIV AIDS and ethics diseases associated with other retroviruses human immunodeficience virus type-2 HTLV-1 and HTLV-2.

Didanosine Resistance in HIV-infected Patients Switched from Zidovudine to Didanosine Monotherapy

Abstract: OBJECTIVE To determine the frequency and pattern of development of specific drug resistance mutations for human immunodeficiency virus (HIV) reverse transcriptase in patients switched from zidovudine to didanosine therapy and to examine the relation of the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase gene to CD4+ T-cell changes and virus burden. DESIGN Retrospective analysis of all patients enrolled at Stanford University in protocols where patients were switched from zidovudine to didanosine monotherapy. SETTING A university hospital. PATIENTS 64 patients infected with HIV who were switched from zidovudine to didanosine monotherapy. Patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex, or were asymptomatic (mean [+/- SD] starting CD4+ T-cell count of 129 +/- 88 cells/mm3). MEASUREMENTS Serial serum specimens were tested for the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase gene and for a zidovudine resistance mutation at codon 215 using selective polymerase chain reactions (PCR). Serum HIV RNA levels were determined by quantitative PCR. CD4+ T-cell counts were determined at serial time points. RESULTS By 24 weeks of didanosine therapy, the proportion of patients with the didanosine resistance mutation at codon 74 increased from 0% to 56% (36 of 64). In contrast, the proportion of patients with the zidovudine resistance mutation at codon 215 decreased from 84% at the start to 59% after 24 weeks of didanosine therapy (a 25% decrease, 95% lower CI, 15%; P < 0.0001). Patients who developed the codon 74 mutation had a greater decrease in CD4+ T cells after the development of the mutation than did patients without the mutation (P < 0.001). In addition, after 24 weeks of didanosine, patients who developed the codon 74 mutation had a greater serum HIV RNA burden than patients who remained wild type (did not have the mutation) at codon 74 (225,000 compared with 82,400 HIV RNA copies/mL serum; P = 0.01). CONCLUSIONS Among patients infected with HIV who had advanced disease and were switched from zidovudine to didanosine therapy, more than one half developed the didanosine resistance mutation at codon 74 by 24 weeks of didanosine therapy. Patients who developed the codon 74 mutation had a greater decline in CD4+ T cells after the development of the mutation and had a greater serum virus burden than did patients without the codon 74 mutation.

Detection Of Drug Resistance Mutations In The Human Immunodeficiency Virus Type I (HIV-I) pol Gene: Differences In Semen And Blood HIV-I RNA And Proviral DNA

Abstract: Different tissues or body fluids in which human immunodeficiency virus type 1 (HIV-1) can reside may contain viruses with distinct characteristics. Sixteen HIV-1-infected patients receiving zidovudine or didanosine were studied cross-sectionally and 1 patient who switched from zidovudine to didanosine was followed sequentially to determine if drug resistance mutations within the HIV-1 pol gene at codons 74 and 215 differed depending on the compartment from which the gene was isolated (plasma, seminal fluid, peripheral blood mononuclear cells, or seminal nonspermatozoal mononuclear cells). Cell-free virus in plasma and semen developed detectable mutations first, followed by proviral DNA in seminal nonspermatozoal and peripheral blood mononuclear cells. Study of the appearance of HIV-1 mutations in various compartments may help elucidate how the populations and dynamics of the virus differ throughout the body and determine whether seminal cell-free virus or provirus is the major sexually transmitted form.

Failure Of Short-Term Cd4-Pe40 Infusions To Reduce Virus Load In Human Immunodeficiency Virus-Infected Persons

Abstract: The safety, immunologic, and antiviral effects of a recombinant biologic product that combines the second and third domains of the CD4 molecule and Pseudomonas exotoxin A (PE40) were evaluated in 21 human immunodeficiency virus (HIV)-infected subjects in a phase III open-label dose-ranging study. Subjects with CD4+ lymphocyte counts of 100-500/mm3 received CD4-PE40 at 40, 80, or 160 micrograms/m2 by infusion three to seven times over 10 days. At the maximum tolerated dose (80 micrograms/m2), peak CD4-PE40 levels were 65-130 ng/mL with a serum half-life of 3.6 +/- 1.5 h. Toxicity, primarily increased hepatic transaminases, was dose-related and reversible. HIV DNA proviral levels in peripheral blood mononuclear cells and plasma HIV RNA remained stable during and after CD4-PE40 infusions. The relative resistance of clinical isolates of HIV, limits of the tolerated dose, and the immunogenicity and short half-life of the protein may explain the lack of in vivo antiviral effect of CD4-PE40.

Diurnal and short-term stability of HIV virus load as measured by gene amplification.

Abstract: To determine whether human immunodeficiency virus (HIV) viral load has short term stability, eight clinically stable subjects infected with HIV and having CD4 counts ranging between 10-600/mm3, had blood samples taken at 0800 and 1700 on 3 consecutive days and then weekly at 0800 for 1 month (8-10 observations/subject). Plasma HIV RNA, peripheral blood mononuclear cell (PBMC) proviral DNA, serum p24 antigen levels, and mononuclear cell subsets were measured at each time point. Mean plasma HIV RNA, PBMC HIV DNA, and p24 antigen [both regular and immune complex dissociated (ICD)] levels did not change significantly between mornings and afternoons or on successive days or weeks. CD4+, CD8+, and CD56+ number demonstrated a diurnal variation in those subjects with > 200 CD4 cells/mm3. We conclude that HIV viral load demonstrates short-term stability in clinically stable subjects. This stability has important implications for monitoring HIV disease progression or antiretroviral therapy.

HIV-1 syncytium-inducing phenotype, virus burden, codon 215 reverse transcriptase mutation and CD4 cell decline in zidovudine-treated patients.

Abstract: The variable rate of disease progression in HIV-1-infected patients treated with zidovudine may be related to certain viral characteristics, such as, antiviral drug resistance, virus burden, and viral syncytium-inducing (SI) capacity. Thirty-two HIV-1-infected patients treated with zidovudine (mean of 34 months) were studied to determine the relationship of SI phenotype and the codon 215 pol gene mutation (a marker of zidovudine resistance) to virus burden and CD4 cell decline. Patients with SI strains and the codon 215 mutation in their proviral DNA had a 54% decline in CD4 cells and a virus burden of 21,480 proviral DNA copies/10(6) CD4 cells. In contrast, patients with non-SI (NSI) strains and wild-type at codon 215 had a 10% increase in CD4 cells and had a viral burden 1/46 that of patients with SI and the 215 mutation. Among patients with NSI strains, changes in CD4 cells depended on the presence of the codon 215 mutation (-160 CD4 cells/microliters), compared with those wild-type at codon 215 (+28 CD4 cells/microliters) (p < 0.01). There was a concordant rise in virus burden between proviral DNA and plasma HIV RNA depending on HIV phenotype and genotype. Using multiple linear regression, SI phenotype and the codon 215 mutation were found to independently predict CD4 cell decline and increased virus burden in zidovudine-treated patients.

Quantitation of Human Immunodeficiency Virus by Culture and Polymerase Chain Reaction in Response to Didanosine after Long-Term Therapy with Zidovudine

Abstract: Measurements of human immunodeficiency virus by quantitative RNA and DNA polymerase chain reaction (PCR), cell and plasma infectivity dilution cultures, and immune complex-disassociated p24 antigen-capture ELISA were made repeatedly in 10 subjects receiving long-term zidovudine treatment before and after therapy was changed to didanosine. Comparison of baseline assays showed that quantitative cell cultures, plasma RNA, and proviral DNA were measurable in all subjects and that cell culture results were significantly correlated with measures of nucleic acids. Plasma viremia (as indicated by culture) and p24 antigen were detected in three measurements in 3 of 8 and 6 of 10 subjects, respectively. Significant decreases in plasma RNA and cell dilution cultures from baseline were maintained for up to 6 months after initiation of didanosine therapy. These findings demonstrate a decrease in virus burden with the use of didanosine; however, continued detection of plasma RNA suggests that additional antiviral therapy will be required to suppress viral replication.

Deficiency In Antibody Response To Human Cytomegalovirus Glycoprotein Gh In Human Immunodeficiency Virus-Infected Patients At Risk For Cytomegalovirus Retinitis

Abstract: Human immunodeficiency virus (HIV)-infected patients at risk for symptomatic human cytomegalovirus (CMV) infection were studied for serum antibody to CMV glycoproteins gH and gB. Antibody titers to gB in HIV-seropositive patients, irrespective of CD4 cell counts or presence of CMV retinitis, were significantly higher than titers in HIV-seronegative, CMV-seropositive patients but were comparable to titers detected in HIV-seronegative patients with CMV mononucleosis. In contrast, antibody to gH was rarely detected in HIV-seropositive patients with CD4 cell counts > 100/mm3 compared with patients with counts > 100/mm3. The inability to detect gH antibody at a time of high risk for symptomatic CMV retinitis suggests that immune intervention with either gH-specific vaccine or passive immunotherapy may benefit HIV-infected persons at risk for symptomatic CMV disease.

Human Immunodeficiency Virus Envelope Glycoproteins

Abstract: Given the long-term clinical latency and high level of replication of human immunodeficiency virus (HIV), it is not surprising that HIV has developed a method of persistence involving production of novel variants in its proteins. Therapeutic vaccines attempt to harness enhanced immune mechanisms to control viral replication, and thus prevent disease progression. A major problem in the development of a vaccine is the great variety of viral quasispecies in HIV infection worldwide and within the lifetime of a given individual. Furthermore, the protective immune parameters that correlate with the ability to control disease progression remain undefined. Manufacturers have followed a number of paths to select an immunogen. At present, investigators are monitoring different immune and viral parameters to measure the effects of therapeutic vaccination. This monitoring ranges from HIV-specific cellular and humoral immunity to viral load markers and skin tests to recall antigens. Two possible major limitations to this treatment approach are the declining potency of the immune response and the ability of the virus to produce escape mutants, particularly during disease progression as viral replication increases. The latter escape mechanism could be similar to the specific pol mutations that enable the virus to escape the impact of drug therapy. Although apparent safety has been observed in phase II/III studies using several HIV envelope-based therapeutic vaccines, investigators have documented reproducible immunogenicity only in HIV-seropositive individuals with CD4+ T cells > 400/mm3. A convincing impact of vaccine therapy on viral load or the course of HIV disease has not been demonstrated.

Zidovudine And Dideoxycytidine Differ In Their Effects On Human Immunodeficiency Virus-Induced Pathologic Activation Of The Immune System

Abstract: When zidovudine and dideoxycytidine (ddC) were given on schedules of 1 week on drug and 1 week off, results differed substantially in effects on HIV (human immunodeficiency virus type 1)-induced immune activation. Zidovudine (200 mg every 4 h) caused marked lowering toward normal of serum neopterin and beta 2-microglobulin within 1 week. This effect was lost within 1 week off zidovudine. Intermittent ddC (0.03 mg/kg every 4 h) had a smaller 1-week effect but had a delayed cumulative suppressive effect on HIV-associated immune activation that was not seen with intermittent zidovudine therapy. Zidovudine and ddC given in alternating weeks had synergistic effects in the first 10 weeks (e.g., early and rapid reduction followed by cumulatively greater effects on immune cell activation). The identical sawtooth effect of intermittent zidovudine was also evident in serum HIV p24 antigen levels. This is consistent with the hypothesis that the increased serum levels of the immune activation markers seen in HIV infection reflect stimulatory effects of HIV viral components on immune system cells.