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Biomedical subjects

Eric S Daar

Publications and source records attributed to Eric S Daar.

At least 37 records · Page 2Linked to original sources
PubMed2005

Primary HIV-1 Infection: Diagnosis, Pathogenesis, and Treatment.

Primary HIV-1 infection represents the time when the virus is first disseminating throughout the body and induces host immune responses. Diagnosing this stage of disease requires an understanding of who is at risk, the clinical manifestations of primary infection, and how the diagnosis is made. Identifying these individuals allows for counseling to prevent further transmission to others and the potential benefits associated with early antiretroviral therapy. Moreover, studying these individuals provides important insight into the biology of HIV-1 transmission and immunopathogenesis.

Journal Article↗
PubMed2005

Diagnostic discordance for hepatitis C virus infection in hemodialysis patients.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with an increase in proinflammatory cytokine levels. Similar changes are seen in maintenance hemodialysis patients with malnutrition-inflammation-cachexia syndrome (MICS), which is associated with poor clinical outcomes in this population. We hypothesized that HCV transcription-mediated amplification (TMA), a sensitive qualitative molecular test for HCV RNA, may identify maintenance hemodialysis patients with HCV infection not detected by means of antibody enzyme immunoassay (EIA), particularly in those with MICS. METHODS: We evaluated HCV status in 314 maintenance hemodialysis patients by using HCV antibody EIA (version 2.0; Abbott Laboratories, Abbott Park, IL) and HCV TMA (Bayer Diagnostics Laboratories, Berkeley, CA). RESULTS: Twenty-five patients (8%) were EIA positive (EIA+)/TMA+; 4 patients (1%), EIA+/TMA negative (TMA-), and 22 patients (7%), EIA-/TMA+. In the 47 TMA+ patients, the sensitivity of EIA for HCV infection was only 53%. TMA+ patients had lower albumin levels and higher tumor necrosis factor alpha and serum glutamic oxaloacetic transaminase levels than TMA- patients. EIA+/TMA+ patients were more likely than EIA-/TMA+ or EIA-/TMA- patients to have hypoalbuminemia and higher iron and transaminase levels. Of all TMA+ patients, EIA- patients were more likely to have diabetes, be on dialysis therapy longer, and have lower liver enzyme levels and higher proinflammatory cytokine levels, including tumor necrosis factor alpha and interleukin 6. CONCLUSION: Maintenance hemodialysis patients infected with HCV according to TMA have clinical features suggestive of MICS. In this population, HCV EIA appears to have a low sensitivity for the identification of HCV infection, which may be caused by the confounding effect of MICS or other demographic or clinical factors. These apparently false-negative HCV antibody test results are seen in persons with a longer time on hemodialysis therapy, mirroring observations in other populations with serious progressive conditions, such as human immunodeficiency virus infection.

Adult↗
PubMed2005

Confronting the emergence of drug-resistant HIV type 1: impact of antiretroviral therapy on individual and population resistance.

Resistance to antiretroviral agents, and in particular the increasing levels of transmitted resistant virus could offset the substantial gains won with potent antiretroviral therapy. Primary and acquired antiretroviral resistance rates reflect the relative usage of different antiretroviral drugs in the population, as well as the inherent genetic barrier to the development of resistance associated with individual drugs. Data on antiretroviral resistance rates, gleaned from the growing HIV-1-infected population treated with a continuously increasing number of antiretroviral drugs and drug combinations, provide insights into patient management approaches for delaying the emergence of resistance and minimizing the degree of resistance. Evolving data suggest that the relative ease by which HIV-1 escapes the selective pressure of chronic drug exposure varies for the different antiretroviral drug classes and individual antiretroviral drugs. The development of resistance in vivo can be anticipated based on these data, in conjunction with the individuals treatment history and resistance testing results. These in turn can guide the judicious use of antiretroviral drugs to attain optimal treatment responses and to preserve therapeutic options for the time when antiretroviral-resistant strains emerge. The recent developments of new antiretroviral drugs, including the use of boosted protease inhibitors, suggest that treatment strategies can limit the development of resistance.

Anti-HIV Agents↗
PubMed2005

Strategies for initiating combination antiretroviral therapy.

Numerous potent antiretroviral regimens have proven successful as initial therapy in treatment-naive HIV-infected patients. As the development of new agents makes possible new treatment regimens, providers are faced with increasingly complex questions of when to initiate treatment and which regimen to select for individual patients. Clinical trial data provide a foundation for choosing an initial regimen and play a key role in the formation of treatment guidelines issued by the United States Public Health Service and other organizations. This paper reviews the results of recent clinical trials focusing on initial therapy and addresses important considerations when beginning antiretroviral therapy (ART) in treatment-naive individuals.

Antiretroviral Therapy, Highly Active↗
PubMed2005

HLA-B63 presents HLA-B57/B58-restricted cytotoxic T-lymphocyte epitopes and is associated with low human immunodeficiency virus load.

Several HLA class I alleles have been associated with slow human immunodeficiency virus (HIV) disease progression, supporting the important role HLA class I-restricted cytotoxic T lymphocytes (CTL) play in controlling HIV infection. HLA-B63, the serological marker for the closely related HLA-B*1516 and HLA-B*1517 alleles, shares the epitope binding motif of HLA-B57 and HLA-B58, two alleles that have been associated with slow HIV disease progression. We investigated whether HIV-infected individuals who express HLA-B63 generate CTL responses that are comparable in breadth and specificity to those of HLA-B57/58-positive subjects and whether HLA-B63-positive individuals would also present with lower viral set points than the general population. The data show that HLA-B63-positive individuals indeed mounted responses to previously identified HLA-B57-restricted epitopes as well as towards novel, HLA-B63-restricted CTL targets that, in turn, can be presented by HLA-B57 and HLA-B58. HLA-B63-positive subjects generated these responses early in acute HIV infection and were able to control HIV replication in the absence of antiretroviral treatment with a median viral load of 3,280 RNA copies/ml. The data support an important role of the presented epitope in mediating relative control of HIV replication and help to better define immune correlates of controlled HIV infection.

Amino Acid Sequence↗
PubMed2005

Human immunodeficiency virus type 1 clade B superinfection: evidence for differential immune containment of distinct clade B strains.

Sequential infection with different strains of human immunodeficiency virus type 1 (HIV-1) is a rarely identified phenomenon with important implications for immunopathogenesis and vaccine development. Here, we identify an individual whose good initial control of viremia was lost in association with reduced containment of a superinfecting strain. Subject 2030 presented with acute symptoms of HIV-1 infection with high viremia and an incomplete seroconversion as shown by Western blotting. A low set point of viremia (approximately 1,000 HIV-1 copies/ml) was initially established without drug therapy, but a new higher set point (approximately 40,000 HIV-1 copies/ml) manifested about 5 months after infection. Drug susceptibility testing demonstrated a multidrug-resistant virus initially but a fully sensitive virus after 5 months, and an analysis of pol genotypes showed that these were two phylogenetically distinct strains of virus (strains A and B). Replication capacity assays suggested that the outgrowth of strain B was not due to higher fitness conferred by pol, and env sequences indicated that the two strains had the same R5 coreceptor phenotype. Delineation of CD8+-T-lymphocyte responses against HIV-1 showed a striking pattern of decay of the initial cellular immune responses after superinfection, followed by some adaptation of targeting to new epitopes. An examination of targeted sequences suggested that differences in the recognized epitopes contributed to the poor immune containment of strain B. In conclusion, the rapid overgrowth of a superinfecting strain of HIV-1 of the same subtype raises major concerns for effective vaccine development.

AIDS Vaccines↗
PubMed2004

Effect of hepatitis C virus (HCV) genotype on HCV and HIV-1 disease.

The relationship between hepatitis C virus (HCV) genotype and HCV and human immunodeficiency virus (HIV) type 1 disease is not well defined. The present study analyzed data from a cohort of 207 HIV-1-infected and 126 HIV-1-uninfected children and adolescents with hemophilia who enrolled in the Hemophilia Growth and Development Study and were followed for 7 years. The mean HCV RNA level was higher in the participants in the HCV genotype 1 group than in the participants the HCV non-genotype 1 group, among both the HIV-1-infected (difference, +0.33 log(10) copies/mL; P=.038) and HIV-1-uninfected (difference, +0.59 log(10) copies/mL; P=.008) participants. Although HCV genotype was not associated with differences in HIV-1 RNA level, a significantly lower mean CD4(+) T cell count (difference, -127 cells/ microL; P=.026) and percentage of CD4(+) T cells (difference, -4.3%; P=.027) were observed in the participants in the HCV genotype 1 group, compared with those in the participants in the HCV non-genotype 1 group. In addition, the participants in the HCV genotype 1 group were at increased risk for progression to AIDS-related mortality (hazard ratio, 2.44; P=.037). The present study suggests that HCV infection and genotype may influence the natural history of HCV and HIV-1 disease.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Growth hormone improves lean body mass, physical performance, and quality of life in subjects with HIV-associated weight loss or wasting on highly active antiretroviral therapy.

HIV-associated wasting is defined as > or = 10% involuntary weight loss and includes declines in both lean and fat mass. This large (757 subjects), randomized, double-blind, placebo-controlled trial investigated the efficacy, safety, and tolerability of recombinant human growth hormone (rhGH) in 2 doses-0.1 mg/kg up to a maximum of 6 mg daily (DD) or alternate days (AD)-in the treatment of wasting and weight loss in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects. The evaluable population for ergometry comprised 555 subjects, 87.6% of whom were receiving HAART. At 12 weeks, median maximum work output increased by 2.4 and 2.6 kJ in the AD and DD groups, respectively. The median treatment difference was 2.9 kJ for DD vs. placebo (P < 0.0001). Body weight increased by 2.2 and 2.9 kg in the AD and DD groups, respectively. Corresponding median treatment differences vs. placebo were 1.5 and 2.2 kg (P < 0.0001). Lean body mass (LBM), by bioelectric impedance spectroscopy, increased by 3.3 and 5.2 kg, respectively (P < 0.0001 vs. placebo; P = 0.0173 DD vs. AD), and fat mass, predominately truncal, decreased. Quality of life (QoL) improved significantly in both rhGH groups. Fluid-retention adverse effects and hyperglycemia were more common in the DD than in the AD group. No significant changes in HIV viral load or CD4 cell count occurred. In conclusion, over the 12-week course of therapy, rhGH, 0.1 mg/kg DD, was superior to placebo in improving physical function, body weight, body composition, and QoL and was superior to AD dosing in restoring LBM.

Adult↗
PubMed2004

Human immunodeficiency virus type 1 (HIV-1) diversity at time of infection is not restricted to certain risk groups or specific HIV-1 subtypes.

African women frequently acquire several genetically distinct human immunodeficiency virus type 1 (HIV-1) variants from a heterosexual partner, whereas the acquisition of multiple variants appears to be rare in men. To determine whether newly infected individuals in other risk groups acquire genetically diverse viruses, we examined the viral envelope sequences in plasma samples from 13 women and 4 men from the United States infected with subtype B viruses and 10 men from Kenya infected with non-subtype B viruses. HIV-1 envelope sequences differed by more than 2% in three U.S. women, one U.S. man, and one Kenyan man near the time of seroconversion. These findings suggest that early HIV-1 genetic diversity is not exclusive to women from Africa or to infection with any particular HIV-1 subtype.

Female↗
PubMed2004

Genetic basis of hypersusceptibility to protease inhibitors and low replicative capacity of human immunodeficiency virus type 1 strains in primary infection.

The initial virus strains from as many as 12% of individuals with primary human immunodeficiency virus (HIV) infection have a 50% inhibitory concentration </=0.4-fold that of HIV type 1(NL4-3) (HIV-1(NL4-3)) to ritonavir (hypersusceptibility [HS]). There is also substantial variation in replicative capacity (RC) or an in vitro assay of the contributions of protease (PR) and reverse transcriptase to viral fitness. In chronically infected antiretrovirally treated patients, amprenavir HS has been associated with the mutation N88S in PR, but this mutation is not seen in untreated patients. In this study, virus strains from 182 cases of primary HIV infection were analyzed, and a highly significant association between HS and low RC (</=10% that of HIV-1(NL4-3)) was observed (P < 10(-6)). Multivariate analysis was used to determine the genotypic basis of ritonavir HS, analyzing all polymorphic amino acid sites and insertions from p7gag through PR. Decision tree models developed on the entire Gag-plus-PR data set and on PR alone gave overall correct classifications of 73 and 72%, respectively, on cross-validation. They were also able to predict low RC, with sensitivities of 69 and 62% and specificities of 84 and 70%, respectively. The analysis shows that ritonavir HS in untreated primary HIV infection is not associated with single mutations but with combinations of amino acids at polymorphic sites and that the same genotypes which confer HS to PR inhibitors confer low RC. This supports the view that variation in PR function is directly responsible for variation in fitness among strains in primary infection.

Decision Trees↗
PubMed2004

What's next? Treatment options when the first antiretroviral regimen fails virologically or is not tolerated, Part 1.

There are many choices for the initial treatment of HIV infection. However, a change may be required if drug resistance or intolerance occurs. Thus, the selection of an initial regimen is important not only because of its immediate effects but also because of its potential influence on subsequent treatment options. HIV clinicians should be aware of the resistance and safety profiles of the regimens they prescribe as initial therapy and be ready with a strategy for subsequent treatment in the event of virologic failure or drug toxicity. This article suggests treatment algorithms for those experiencing adverse events or the emergence of drug resistance with commonly used antiretroviral regimens.

Algorithms↗
PubMed2004

What's next? Treatment options when the first antiretroviral regimen fails virologically or is not tolerated, Part 2.

As outlined in Part 1 of this 2-part review, there are many choices for the initial treatment of HIV infection. The Department of Health and Human Services HIV treatment guidelines include regimens that are "preferred" or "alternative" for initial therapy. In Part 2 of this review, we discuss those regimens that are considered alternatives, as well as emerging combinations that may be considered for inclusion in future treatment guidelines. With any of these treatments, a change in therapy may be required if drug resistance or intolerance occurs. An initial regimen is important because of its immediate effects and potential influence on the utility of subsequent treatment options. HIV clinicians should be aware of the resistance and safety profiles of all of the various regimens they may prescribe as initial therapy and should be ready to employ a strategy for subsequent treatment in the event of virologic failure or the development of drug toxicity. This article builds on Part 1 by suggesting treatment algorithms for those experiencing adverse events or the emergence of drug resistance when using recommended or common alternative and emerging anti-HIV regimens.

Algorithms↗
PubMed2003

Transmission fitness of drug-resistant human immunodeficiency virus and the prevalence of resistance in the antiretroviral-treated population.

Although the prevalence of drug-resistant strains in primary human immunodeficiency virus (HIV) infection in North America has recently increased, their transmission fitness remains unknown. The present study estimated the frequency of transmission of drug-resistant HIV from patients receiving antiretroviral therapy using retrospective surveys of clinic data. It revealed that resistant virus was transmitted only approximately 20% as frequently as expected from these patients. Individuals with primary resistance may become a significant source of resistant strains.

Anti-HIV Agents↗
PubMed2003

Improving adherence to antiretroviral therapy.

Taking antiretroviral medications as directed is essential to reducing the plasma viral load. By controlling HIV replication, antiretroviral combination therapy enables the host's immune system to fortify itself and ward off opportunistic pathogens. However, adhering to antiretroviral regimens that include at least 3 different drugs taken once, twice, or 3 times a day is a constant challenge for patients with HIV disease. Care providers need to be aware of the challenges and obstacles faced by their patients on antiretroviral regimens, and efforts to maximize adherence must begin even before the patient has the first prescriptions filled.

Anti-HIV Agents↗