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Biomedical subjects

Charles B Hicks

Publications and source records attributed to Charles B Hicks.

At least 19 recordsLinked to original sources
PubMed2007

Detection of minor drug-resistant populations by parallel allele-specific sequencing.

We developed a highly sensitive parallel allele-specific sequencing (PASS) assay to simultaneously analyze a large number of viral genomes and detect minor drug-resistant populations at approximately 0.1-0.01% levels. Using this assay on samples from individuals infected with human immunodeficiency viruses (HIV), we successfully detected and quantified minor populations of drug-resistant viruses and performed linkage analysis of multiple-drug resistance mutations. This assay may serve as a useful tool to study drug resistance in HIV and other infectious agents.

Anti-HIV Agents↗
PubMed2006

Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials.

BACKGROUND: Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients. METHODS: We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log(10) copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2). FINDINGS: 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65.1%) patients on tipranavir-ritonavir and 192 (26.1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33.6%] vs 113 [15.3%]; p<0.0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0.0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group. INTERPRETATION: Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.

Adult↗
PubMed2005

Safety and antiviral activity of lopinavir/ritonavir-based therapy in human immunodeficiency virus type 1 (HIV-1) infection.

Protease inhibitor-based antiretroviral therapy has been shown to decrease the morbidity and mortality associated with human immunodeficiency virus type 1 (HIV-1) infection. However, many of the available agents in this class suffer shortcomings, including poor tolerability, difficult dosing regimens, and variable drug concentrations which may lead to generation of viral resistance. Lopinavir/ritonavir (Kaletra) has been designed specifically to address some of these shortcomings. Excellent therapeutic efficacy has been documented for lopinavir/ritonavir in multiple clinical trials in both antiretroviral-naive and -experienced patients. Development of resistance is a rare event in persons initiating therapy with lopinavir/ritonavir as their first protease inhibitor. The main side effects associated with lopinavir/ritonavir are gastrointestinal disturbances and elevations of serum lipids. Current antiretroviral therapy guidelines list lopinavir/ritonavir as the consensus first-line protease inhibitor recommended in the initial therapeutic regimen in persons infected with HIV-1.

Anti-HIV Agents↗
PubMed2005

Naïve T cells are maintained in the periphery during the first 3 months of acute HIV-1 infection: implications for analysis of thymus function.

A key determinant of T cell dynamics in HIV-1 infection is the status of thymic function. To date, most studies of the impact of HIV-1 on the thymus during early HIV-1 infection have been done in samples collected in the interval of 3-12 months after infection. In this study, we have probed the status of thymic function and peripheral naive T cells in patients with acute HIV-1 infection diagnosed 18-72 days after the onset of symptoms. We found that peripheral CD4 and CD8 T cell proliferation was initially elevated, then waned over time. The fall in T cell proliferation correlated with a reduction in HIV-1 viral RNA levels and a rise in peripheral blood CD4+ CD25+ T cells. In spite of elevated T cell proliferation early on in primary HIV-1 infection, levels of naive phenotype CD4 and CD8 T cells and T cell receptor excision circle positive cells (sjTREC(+)) remained constant. Taken together with the observation that T cell proliferation normally dilutes peripheral T cell episomal sjTREC levels, these data suggested that thymopoiesis contributes to maintenance of the naive T cell pool during the earliest stages of HIV-1 infection (18-72 days).

Adult↗
PubMed2005

Longitudinal assessment of immune response and viral characteristics in HIV-infected patients with prolonged CD4(+)/viral load discordance.

Although suppression of HIV-1 RNA below the limit of detection is associated with optimal outcomes, many patients can maintain or increase their CD4(+) count for prolonged time periods in the presence of persistent low-level viremia. We followed seven patients with prolonged (>5 years) discordant CD4(+)/viral load (VL) responses on protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) prospectively for 1 year to assess evolution of immune function, viral phenotype, replication capacity (RC), and resistance profile. Immune function was assessed by qualitative and quantitative measurement of cellular activation (CD38(+)HLA-DR(+) and CD38 antibodies bound per cell), and the interferon (IFN)-() ELISpot assay. Presence of syncytium-inducing (SI) or nonsyncytium-inducing (NSI) viral strains was determined by MT-2 cell culture. RC was measured by a modified rapid recombinant virus assay. The resistance profile was characterized by both genotypic and phenotypic analysis. Over the year of follow-up, IFN-() production to gag persisted, responses to other HIV antigens increased, and markers of cellular activation did not change. NSI virus predominated. The genotypic (GSS) and phenotypic (PSS) susceptibility scores remained stable. Evolution of RC was variable over the year of follow-up, but the RC of viruses remained well below that of wild-type clinical isolates. Thus, CD4(+)/VL discordance can be maintained for periods exceeding 5 years in some patients receiving PI-based HAART without significant evolution of HIV resistance.

Adolescent↗
PubMed2005

Lopinavir/ritonavir in the treatment of human immunodeficiency virus infection.

The importance of combination antiretroviral therapy in HIV-infection has been well established. However, many available agents suffer shortcomings that limit their clinical value, including adverse effects, difficult dosing requirements and rapid development of resistance. Lopinavir/ritonavir (Kaletra) is a member of the protease inhibitor class, specifically designed to address some of these deficits. The drug is a coformulation of lopinavir with low-dose ritonavir, exploiting a favourable drug-drug interaction between the two that yields sustained increases in plasma levels of lopinavir. In large-scale clinical trials, lopinavir/ritonavir has demonstrated superior therapeutic efficacy when compared with other protease inhibitors. It exerts potent antiviral activity in both treatment-naive and experienced patients with an acceptable incidence of adverse effects. De novo development of resistance has not been described in large clinical trials with patients naive to antiretroviral therapy. Lopinavir/ritonavir has recently been approved for once-daily dosing in antiretroviral-naive patients.

Administration, Oral↗
PubMed2004

Multiple V1/V2 env variants are frequently present during primary infection with human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 (HIV-1) exists as a complex population of multiple genotypic variants in persons with chronic infection. However, acute HIV-1 infection via sexual transmission is a low-probability event in which there is thought to be low genetic complexity in the initial inoculum. In order to assess the viral complexity present during primary HIV-1 infection, the V1/V2 and V3 variable regions of the env gene were examined by using a heteroduplex tracking assay (HTA) capable of resolving these genotypic variants. Blood plasma samples from 26 primary HIV-1-infected subjects were analyzed for their level of diversity. Half of the subjects had more than one V1/V2 viral variant during primary infection, indicating the frequent transmission of multiple variants. This observation is inconsistent with the idea of infrequent transmission based on a small transmitting inoculum of cell-free virus. In chronically infected subjects, the complexity of the viral populations was even greater in both the V1/V2 and the V3 regions than in acutely infected subjects, indicating that in spite of the presence of multiple variants in acute infection, the virus does pass through a genetic bottleneck during transmission. We also examined how well the infecting virus penetrated different anatomical compartments by using the HTA. Viral variants detected in blood plasma were compared to those detected in seminal plasma and/or cerebral spinal fluid of six individuals. The virus in each of these compartments was to a large extent identical to virus in blood plasma, a finding consistent with rapid penetration of the infecting variant(s). The low-probability transmission of multiple variants could be the result of transient periods of hyperinfectiousness or hypersusceptibility. Alternatively, the inefficient transfer of a multiply infected cell could account for both the low probability of transmission and the transfer of multiple variants.

Acute Disease↗
PubMed2003

Envelope diversity, coreceptor usage and syncytium-inducing phenotype of HIV-1 variants in saliva and blood during primary infection.

OBJECTIVE: To determine whether oral fluids can serve as a model for studying HIV-1 shedding, we compared the genetic diversity, coreceptor use, and syncytium-inducing (SI) phenotype of viral variants in saliva and blood during primary HIV-1 infection. DESIGN: Observational cross-sectional cohort study. METHODS: Blood plasma and saliva were sampled from 17 men early in primary HIV-1 infection. Viral diversity, predicted X4/R5 genotype and SI phenotype in samples were determined by heteroduplex tracking assays (HTAs) targeting the V1/V2 and V3 gp120 regions, sequence analyses and MT-2 cell assay. RESULTS: Identical or very similar HTA banding and deduced amino acid sequence patterns in the V1/V2 and V3-encoding regions were observed between paired fluids of each subject. As assessed by V1/V2 HTA, 10 subjects had a single major viral variant and seven subjects exhibited multiple yet highly related variants. Two subjects had V1/V2 variants in blood that were identical to saliva but present in different relative abundances. A sexual transmission pair exhibited genetically dissimilar variants, suggesting transmission of a minor variant or rapid evolution during initial viremia. All subjects harbored R5 non-SI variants. CONCLUSIONS: Relatively homogenous viral populations detected in plasma and saliva prior to seroconversion suggests that HIV-1 is disseminated to oral fluids early in infection and reflects the quasispecies in blood. These findings suggest that the oral cavity may serve as an easily accessible surrogate model for studying the dynamics of HIV-1 shedding at mucosal sites.

Adult↗
PubMed2003

Infrequent diagnosis of primary human immunodeficiency virus infection: missed opportunities in acute care settings.

Although primary human immunodeficiency virus infection (PHI) is usually symptomatic and early management is likely important, the diagnosis is infrequently made. We examined a prospectively enrolled cohort of individuals diagnosed as having PHI in the southeastern United States to determine problems associated with the diagnosis of PHI. The following information was collected on each individual: site of initial presentation, number of visits to health care settings before diagnosis, diagnosing physician, alternative diagnoses, presumptive therapies, and time to diagnosis of PHI. Data were available for 29 of 30 patients (17 white, 12 nonwhite). Most patients were seen at least 3 times before the diagnosis of PHI was made. White persons were seen more frequently by primary care providers (P =.09). Nonwhite persons were diagnosed more quickly (P =.045). Only 5 patients (17%) were correctly diagnosed during their first encounter with the health care system, while 5 (17%) remained undiagnosed for more than 1 month after first presentation. Infectious diseases specialists diagnosed 83% of the cases. Human immunodeficiency virus is infrequently diagnosed during primary infection. More expeditious diagnosis of human immunodeficiency virus infection is a clinical and public health imperative.

Adult↗
PubMed2003

Prolonged CD4+ cell/virus load discordance during treatment with protease inhibitor-based highly active antiretroviral therapy: immune response and viral control.

Mechanisms that underly discordant CD4+ cell/virus load (VL) responses in patients who receive highly active antiretroviral therapy (HAART) were studied in 30 human immunodeficiency virus (HIV)-positive patients, in 3 groups. Discordant responders maintained CD4+ cell levels >200/mm(3) with stable or increasing trend, despite sustained VLs of 500-5000 copies/mL, for >2 years. Treatment-success patients had CD4+ cell counts >200/mm(3) with stable or increasing trend and VLs <50 copies/mL, for >2 years. Treatment-failure patients initially responded to HAART, followed by decreasing CD4+ cell counts and increasing VLs. Interferon-gamma production to gag and noncytolytic CD8+ cell suppressive activity were greater in discordant responders. Cellular activation was greatest in patients with treatment failure. All discordant responders had non-syncytium-inducing (CCR5-tropic) viruses. Viruses from discordant responders and from patients with treatment failure had extensive resistance mutations; discordant responders had significantly lower viral replication capacities. These findings suggest that discordant responses may be related to enhanced HIV-directed immune responses, diminished cellular activation, decreased viral replication capacity, and preservation of non-syncytium-inducing virus strains.

Adult↗
PubMed2002

Real-time, universal screening for acute HIV infection in a routine HIV counseling and testing population.

CONTEXT: Acute human immunodeficiency virus (HIV) infection cannot be diagnosed by routine antibody tests and is rarely diagnosed in clinical practice. However, HIV nucleic acid-based testing is widely used to screen for antibody-negative acute infection among low-risk blood donors. OBJECTIVE: To assess the feasibility of screening in high-volume laboratories for acute and long-term HIV infection in a routine HIV testing population, in which HIV infection prevalence is low, using specimen pooling and HIV RNA reverse transcriptase-polymerase chain reaction (RT-PCR) tests. DESIGN AND SETTING: Clinical diagnostic performance evaluation at a state-funded public health virology and serology laboratory. PARTICIPANTS: A total of 8505 consecutive individuals presenting for routine HIV counseling and testing during a total of 20 business days to simulate a month of testing in August and December 2001 at 110 publicly funded testing sites in North Carolina. MAIN OUTCOME MEASURES: Prevalence of acute and long-term HIV infection. Serum specimens negative by HIV enzyme immunoassay (EIA) were screened in pools by an ultrasensitive HIV RNA RT-PCR test. Results for individual HIV RNA-positive specimens were reclassified as true or false according to results of confirmatory testing. RESULTS: Of the 8505 individuals screened, 8194 had not previously tested HIV positive and had sufficient serum to complete the testing protocol. Of those, 39 had long-term HIV infection (prevalence, 47.6 per 10,000 at-risk persons [95% confidence interval, 33.8-65.0 per 10,000]). Of the 8155 at-risk individuals whose antibody tests were negative, 5 were HIV RNA positive. Four of those had true-positive acute infection (prevalence, 4.9 per 10,000 [95% confidence interval, 1.3-12.5 per 10,000]). All 4 were women; 2 developed symptoms consistent with an acute retroviral syndrome in the week after testing. Screening all specimens required 147 HIV RNA tests. Overall specificity of the strategy was 0.9999. CONCLUSIONS: These findings suggest the widespread diagnosis of acute HIV infections in a routine testing population is not only possible but feasible using specimen pooling and nucleic acid testing. These additional procedures may increase diagnostic yield by approximately 10% compared with conventional HIV antibody testing.

AIDS Serodiagnosis↗