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Biomedical subjects

E S Daar

Publications and source records attributed to E S Daar.

At least 19 recordsLinked to original sources
PubMed2001

Relation between HIV-1 and hepatitis C viral load in patients with hemophilia.

Coinfection with hepatitis C virus (HCV) and HIV-1 is common in patients with hemophilia and in intravenous drug users. Little, however, is known about the relation between HIV-1 and HCV coinfection and the effects on HCV clearance and pathogenesis. We examined data from 207 HIV-1-infected and 126 HIV-1-uninfected patients with hemophilia enrolled in the multicenter Hemophilia Growth and Development Study. Participants were observed during prospective follow-up for approximately 7 years with annual measurements of alanine aminotransferase (ALT), CD4+ cells, and HCV and HIV-1 RNA levels. Clearance of HCV was more likely to occur in those uninfected with HIV-1 (14.3 versus 2.5%; odds ratio [OR] 4.79; 95% confidence interval [CI], 1.63-14.08, p =.005) and was more common with decreasing age (OR, 1.23; 95% CI, 1.04-1.47; p =.017). HCV RNA levels were higher throughout the 7 years of follow-up in those HIV-1-infected (p <.001). In the HIV-1-infected participants, baseline CD4+ cells were inversely related to HCV RNA with every 100-cell increase associated with a 0.19 log10 copy/ml decrease in HCV RNA (p =.002), and HIV-1 and HCV RNA levels were directly related (p =.008). Increasing HCV RNA levels were also associated with significantly higher ALT levels regardless of HIV-1 infection status. These results demonstrate that HIV-1/HCV co-infection is associated with a reduced likelihood of HCV clearance and that higher levels of HCV RNA are associated with increased hepatic inflammation.

Adolescent↗
PubMed2001

Hepatitis C virus load is associated with human immunodeficiency virus type 1 disease progression in hemophiliacs.

Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) coinfection is common in hemophiliacs and injection drug users. To assess the interaction between HCV load and HIV-1 disease progression, we examined 207 HIV-1/HCV-coinfected patients. Patients were followed prospectively for approximately 7 years, and annual measurements of CD4(+) cell counts and HCV and HIV-1 loads were obtained. Survival analysis was used to define the independent effects of HCV load on HIV-1 progression. After controlling for CD4(+) cell count and HIV-1 RNA level, every 10-fold increase in baseline HCV RNA was associated with a relative risk (RR) for clinical progression to acquired immunodeficiency syndrome (AIDS) of 1.66 (95% confidence interval [CI], 1.10-2.51; P=.016) and an RR for AIDS-related mortality of 1.54 (95% CI, 1.03-2.30; P=.036). These findings emphasize the need for further research regarding the use of HIV-1- and HCV-specific therapy in coinfected individuals.

Adolescent↗
PubMed2001

Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network.

BACKGROUND: The optimal approach for diagnosing primary HIV-1 infection has not been defined. OBJECTIVE: To determine the usefulness of symptoms and virologic tests for diagnosing primary HIV-1 infection. DESIGN: Prospective cohort study. SETTING: A teaching hospital in Los Angeles and a university research center in San Diego, California. PATIENTS: 436 patients who had symptoms consistent with primary HIV infection. MEASUREMENTS: Clinical information and levels of HIV antibody, HIV RNA, and p24 antigen. RESULTS: Primary infection was diagnosed in 54 patients (12.4%). The sensitivity and specificity of the p24 antigen assay were 88.7% (95% CI, 77.0% to 95.7%) and 100% (CI, 99.3% to 100%), respectively. For the HIV RNA assay, sensitivity was 100% and specificity was 97.4% (CI, 94.9% to 98.9%). Fever, myalgia, rash, night sweats, and arthralgia occurred more frequently in patients with primary infection (P < 0.05). CONCLUSIONS: No sign or symptom allows targeted screening for primary infection. Although assays for HIV RNA are more sensitive than those for p24 antigen in diagnosing primary infection, they are more expensive and are more likely to yield false-positive results.

Antibodies, Viral↗
PubMed2001

The epidemiology of invasive pulmonary aspergillosis at a large teaching hospital.

OBJECTIVE: To characterize the epidemiology of invasive pulmonary aspergillosis (IPA). DESIGN: A retrospective case series. SETTING: An 850-bed, academic, tertiary-care medical center. PARTICIPANTS: Adult inpatients, between January 1, 1990, and December 31, 1998, with either a histopathology report consistent with IPA or a discharge diagnosis of aspergillosis. METHODS: We reviewed medical records and categorized case-patients as definitive or probable and acquisition of IPA as nosocomial, indeterminate, or community using standard definitions. To determine the rate of aspergillus respiratory colonization, we identified all inpatients who had a respiratory culture positive for Aspergillus species without a histopathology report consistent with IPA or a discharge diagnosis of aspergillosis. Three study intervals were defined: interval 1, 1990 to 1992; interval 2, 1993 to 1995; and interval 3, 1996 to 1998. Carpeting in rooms for patients following heart-lung and liver transplant was removed and ceiling tiles were replaced during interval 1; a major earthquake occurred during interval 2. RESULTS: 72 case-patients and 433 patients with respiratory colonization were identified. Acquisition was nosocomial for 18 (25.0%), indeterminate for 9 (12.5%), and community-acquired for 45 (62.5%) case-patients. Seventeen (23.6%) of the 72 case-patients had prior transplants, including 15 solid organ and 2 bone marrow. The IPA rate per 100 solid organ transplants (SOTs) decreased from 2.45 during interval 1 to 0.93 during interval 2 and to 0.52 during interval 3 (chi-square for trend, 5.44; P<.05). The hospitalwide IPA rate remained stable at 0.03 per 1,000 patient days. CONCLUSIONS: The SOT IPA rate decreased after intervals 1 and 2, although the hospitalwide IPA rate remained stable during the study period. Post-earthquake hospital demolition and construction occurring after interval 2 was not associated with an increase in the rate of IPA at our institution.

Adult↗
PubMed2001

Antibody from patients with acute human immunodeficiency virus (HIV) infection inhibits primary strains of HIV type 1 in the presence of natural-killer effector cells.

The partial control of viremia during acute human immunodeficiency virus type 1 (HIV-1) infection is accompanied by an HIV-1-specific cytotoxic T-lymphocyte (CTL) response and an absent or infrequent neutralizing antibody response. The control of HIV-1 viremia has thus been attributed primarily, if not exclusively, to CTL activity. In this study, the role of antibody in controlling viremia was investigated by measuring the ability of plasma or immunoglobulin G from acutely infected patients to inhibit primary strains of HIV-1 in the presence of natural-killer (NK) effector cells. Antibody that inhibits virus when combined with effector cells was present in the majority of patients within days or weeks after onset of symptoms of acute infection. Furthermore, the magnitude of this effector cell-mediated antiviral antibody response was inversely associated with plasma viremia level, and both autologous and heterologous HIV-1 strains were inhibited. Finally, antibody from acutely infected patients likely reduced HIV-1 yield in vitro both by mediating effector cell lysis of target cells expressing HIV-1 glycoproteins and by augmenting the release of beta-chemokines from NK cells. HIV-1-specific antibody may be an important contributor to the early control of HIV viremia.

Antibody-Dependent Cell Cytotoxicity↗
PubMed2001

The effect of plasma human immunodeficiency virus RNA and CD4(+) T lymphocytes on growth measurements of hemophilic boys and adolescents.

OBJECTIVE: The investigation examined the associations of plasma human immunodeficiency virus (HIV) RNA and CD4(+) T lymphocytes with height, weight, skeletal maturation, testosterone levels, and height velocity for hemophilic children and adolescents with HIV infection in the Hemophilia Growth and Development Study. STUDY DESIGN: Two hundred seven participants were evaluated over 7 years. RESULTS: A threefold increment in baseline plasma HIV RNA was associated with a 0.98-cm decrease in height and a 1.67-kg decrease in weight; 100-cells/microL decrements in baseline CD4(+) were associated with a 2.51-cm decrease in height and a 3.83-kg decrease in weight. Participants with high plasma HIV RNA (>3125 copies/mL) experienced significant delay in achieving maximum height velocity and lower maximum velocity compared with those with low viral load. The high CD4(+) (>243)/low plasma HIV RNA group had earlier age at maximum height velocity compared with the other 3 groups and higher maximum height velocity compared with the low CD4(+)/high plasma HIV RNA and low CD4(+)/low plasma HIV RNA groups. Decrements in CD4(+) were associated with decreases in bone age and testosterone level. CONCLUSIONS: CD4(+) and HIV RNA were important in predicting growth outcomes.

Adolescent↗
PubMed2000

HIV-1 protease inhibitors decrease proliferation and induce differentiation of human myelocytic leukemia cells.

Inhibitors of the protease of human immunodeficiency virus type 1 (HIV-1) may inhibit cytoplasmic retinoic acid-binding proteins, cytochrome P450 isoforms, as well as P-glycoproteins. These features of the protease inhibitors might enhance the activity of retinoids. To explore this hypothesis, myeloid leukemia cells were cultured with all-trans retinoic acid (ATRA) either alone or in combination with the HIV-1 protease inhibitors indinavir, ritonavir, and saquinavir. Consistent with the hypothesis, the HIV-1 protease inhibitors enhanced the ability of ATRA to inhibit growth and induce differentiation of HL-60 and NB4 myeloid leukemia cells, as measured by expression of CD11b and CD66b cell surface antigens, as well as reduction of nitroblue tetrazolium. Growth of ATRA-resistant UF-1 cells was also inhibited when cultured with the combination of ATRA and indinavir. Moreover, indinavir enhanced the ability of ATRA to induce expression of the myeloid differentiation-related transcription factor C/EBPepsilon messenger RNA in NB4 cells by 9.5-fold. Taken together, the results show that HIV-1 protease inhibitors enhance the antiproliferative and differentiating effects of ATRA on myeloid leukemia cells. An HIV-1 protease inhibitor might be a useful adjuvant with ATRA for patients with acute promyelocytic leukemia and possibly retinoid-resistant cancers.

CCAAT-Enhancer-Binding Proteins↗
PubMed2000

Modeling plasma virus concentration during primary HIV infection.

During primary HIV infection the viral load in plasma increases, reaches a peak, and then declines. Phillips has suggested that the decline is due to a limitation in the number of cells susceptible to HIV infection, while other authors have suggested that the decline in viremia is due to an immune response. Here we address this issue by developing models of primary HIV-1 infection, and by comparing predictions from these models with data from ten anti-retroviral, drug-naive, infected patients. Applying nonlinear least-squares estimation, we find that relatively small variations in parameters are capable of mimicking the highly diverse patterns found in patient viral load data. This approach yields an estimate of 2.5 days for the average lifespan of productively infected cells during primary infection, a value that is consistent with results obtained by drug perturbation experiments. We find that the data from all ten patients are consistent with a target-cell-limited model from the time of initial infection until shortly after the peak in viremia. However, the kinetics of the subsequent fall and recovery in virus concentration in some patients are not consistent with the predictions of the target-cell-limited model. We illustrate that two possible immune response mechanisms, cytotoxic T lymphocyte destruction of infected target cells and cytokine suppression of viral replication, could account for declines in viral load data not predicted by the original target-cell-limited model. We conclude that some additional process, perhaps mediated by CD8+ T cells, is important in at least some patients.

Cytokines↗
PubMed2000

Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) from patients with primary HIV infection to nonnucleoside reverse transcriptase inhibitors is associated with variation at novel amino acid sites.

Recently, significant numbers of individuals with primary human immunodeficiency virus (HIV) infection have been found to harbor viral strains with reduced susceptibility to antiretroviral drugs. In one study, HIV from 16% of such antiretroviral-naive individuals was shown to have a susceptibility to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) between 2.5- and 10-fold lower than that of a wild-type control. Mutations in the RT domain that had previously been associated with antiretroviral resistance were not shared by these strains. We have analyzed by logistic regression 46 variable amino acid sites in RT for their effect on susceptibility and have identified two novel sites influencing susceptibility to NNRTIs: amino acids 135 and 283 in RT. Eight different combinations of amino acids at these sites were observed among these patients. These combinations showed a 14-fold range in mean susceptibility to both nevirapine and delavirdine. In vitro mutagenesis of the control strain combined with a phenotypic assay confirmed the significance of amino acid variation at these sites for susceptibility to NNRTIs.

Amino Acid Substitution↗
PubMed2000

Dual protease inhibitor therapy in the management of the HIV-1.

Throughout the first 20 years of the HIV-1 epidemic, there have been tremendous advances in the development of antiretroviral therapy (ART). In 1995, the availability of protease inhibitors (PI) as part of triple drug regimens resulted in durable viral suppression with an associated decline in HIV-1-related morbidity and mortality. Despite this early success, limitations of therapy have become apparent. In particular, the need for highly potent antiviral regimens, the importance of outstanding adherence to therapy, drug-related toxicity and the increasing problem of drug-drug and drug-food interactions. Dual PI therapy has been investigated with the hope of overcoming these problems. Select PI combinations may result in synergistic antiviral activity with enhanced viral suppression. Moreover, the ability of select agents to inhibit the cytochrome P450 (CYP450) system results in pharmacologic enhancement that allows for dosing with fewer pills on a less frequent basis, both of which can enhance drug adherence. Furthermore, these pharmacologic interactions can overcome drug-drug and drug-food interactions. Finally, the ability to increase drug levels using certain PI combinations may allow for drug concentrations to exceed those needed to inhibit resistant strains of HIV-1. The rationale for using dual PI therapy, along with the results of clinical trials using various PI combinations in treatment-naïve and experienced patients, is reviewed in this article.

Drug Combinations↗
PubMed2000

Primary HIV infection. Current trends in transmission, testing, and treatment.

In the changing kaleidoscope of HIV disease, early detection of primary infection has become increasingly important. Primary care physicians who recognize the signs and symptoms are in an ideal position to diagnose the disease at an early stage and to help stem the tide of new infections in the community. In this article, Drs Yu and Daar discuss current strategies for early diagnosis, including recommended testing and steps to prevent transmission of the virus, and present the latest thinking about antiretroviral therapy during primary HIV infection.

HIV Infections↗
PubMed1999

Effects of plasma HIV RNA, CD4+ T lymphocytes, and the chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. Hemophilia Growth and Development Study.

We have investigated the effects of plasma HIV RNA, CD4+ T lymphocytes and chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. We prospectively observed during follow-up 207 HIV-infected hemophiliacs in the Hemophilia Growth and Development Study. Plasma HIV RNA was measured on cryopreserved plasma from enrollment using the Chiron Corporation bDNA (version 2.0) assay. Genoytpe variants CCR2b-641 and CCR5-delta32 were detected using standard molecular techniques. Those with the mutant allele for CCR2b, and to a lesser extent CCR5, had lower plasma HIV RNA, and higher CD4+ T lymphocytes than did those without these genetic variants. After controlling for the effects of plasma HIV RNA and CD4+ T lymphocytes, those with the CCR2b mutant allele compared with those wild-type, had a trend toward a lower risk of progression to AIDS, adjusted relative hazard of 1.94 (95% confidence interval [CI], 0.9-4.18; p = .092), and AIDS-related death, relative hazard 1.97 (95% CI, 0.98-4.00; p = .059). We conclude that plasma HIV RNA, CD4+ T lymphocytes, and CCR genotypes are correlated, and the protective affect of CCR2b against HIV disease progression is not completely explained by plasma HIV RNA or CD4+ T-lymphocyte number.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Increased CD4+ T-lymphocyte senescence fraction in advanced human immunodeficiency virus type 1 infection.

Human immunodeficiency virus type 1 (HIV-1) infection is accompanied by peripheral CD4+ T-cell losses. CD4+ T-cell numbers often increase during antiviral treatment of acquired immune deficiency syndrome (AIDS), however, alterations in the CD4+ T-cell repertoire have not been completely corrected for these patients. Such individuals remain at increased risk of infection. Although senescence of the CD4+ T cells has not been adequately evaluated for advanced HIV-1 infection, hypothetically, replicative senescence could complicate therapeutic reconstitution of the CD4+ T cells in AIDS. In this study, correlates of replicative senescence, terminal restriction fragment (TRF) length and percentage short (< 5.0 kb) telomeric DNA (senescence fraction), were measured for the CD4+ T cells of HIV-1-infected patients with peripheral CD4+ T-cell counts of < 200/mm3. The results show that for advanced HIV-1 infection the TRF length of the CD4+ T cells is decreased (P < 0.01), and the senescence fraction increased (P < 0.05), when compared with uninfected controls. These findings suggest that cellular senescence may contribute to disruption of CD4+ T-cell diversity observed following the therapeutic, immunologic reconstitution of AIDS.

Adult↗