Biomedical subjects

Susan Fiscus

Publications and source records attributed to Susan Fiscus.

11 recordsLinked to original sources

PubMed2005

Timing of maternal and neonatal dosing of nevirapine and the risk of mother-to-child transmission of HIV-1: HIVNET 024.

OBJECTIVE: Despite a growing emphasis worldwide on complex and potent antiretroviral drug regimens for the prevention of mother-to-child transmission of HIV-1 (MTCT), two-dose nevirapine (NVP) prophylaxis remains an important choice in many settings. We analyzed data from a multicenter clinical trial to determine whether timing of maternal or infant NVP was associated with MTCT between delivery and 6 weeks of age (intrapartum/early postnatal transmission; I/EP). METHODS: HIVNET 024 was a placebo-controlled, double-blind trial of empiric antibiotics to reduce chorioamnionitis-associated MTCT. This secondary analysis used data collected in the original randomized trial. Enrolled women were instructed to self-administer NVP at labor onset; infants were to receive a dose within 72 h of birth. RESULTS: Data regarding 1491 mother-infant pairs were analyzed. The overall I/EP HIV-1 transmission rate was 8.1% at 6 weeks. Almost all women (93%) ingested NVP within 24 h of delivery; 90% of infants were given NVP within 48 h after delivery. Variations in mother or infant dose timing did not influence transmission rates, even when the combined pattern of both was taken into account through multivariate analysis. In the subset of women ingesting NVP or= 4 h). CONCLUSION: Variations in the timing of maternal and infant NVP doses (within reasonable proximity to delivery) do not appear to affect the risk of MTCT.

Anti-HIV Agents↗

PubMed2005

Cytomegalovirus viremia, mortality, and end-organ disease among patients with AIDS receiving potent antiretroviral therapies.

OBJECTIVE: To determine the association of cytomegalovirus (CMV) viremia with CMV disease and death in patients with AIDS. DESIGN AND SETTING: Prospective, observational cohort study conducted at a university hospital. METHODS: A cohort of 190 subjects with AIDS who were CMV seropositive and had no history or evidence of CMV disease were longitudinally evaluated for signs and symptoms of CMV disease and CMV viremia with plasma CMV DNA polymerase chain reaction (PCR) and whole blood CMV hybrid capture. RESULTS: A total of 187 subjects had at least 1 study visit following entry. At baseline, the median CD4 cell count and plasma HIV RNA level were 110/microL (range = 3-620/microL) and 47,973 copies/mL (<30- >750,000 copies/mL), respectively. Highly active antiretroviral therapy (HAART) use increased from 87.5% during the 1st study year to 98.5% by the end of the study. During a median follow-up of 334 days, 16% (30) of the subjects died and 2 (6%) developed CMV disease. No deaths were attributable to CMV disease; 4 subjects who died developed CMV prior to death. Baseline HIV viral load and final CD4 cell count were significantly and independently associated with mortality. Detectable plasma CMV DNA PCR was an independent predictor of death even after adjusting for HIV RNA level and CD4 cell count prior to death (P = 0.038). In contrast, whole blood CMV hybrid capture did not predict mortality. The CMV assays neither collectively nor individually were found to be associated with the few cases of CMV disease. CONCLUSIONS: In patients with AIDS and seropositive for CMV, detection of CMV viremia with plasma CMV DNA PCR was predictive of death and provided additional prognostic information on the risk of all cause-mortality beyond that obtained with CD4 cell count and HIV viral load testing alone. Detection of CMV viremia by plasma with CMV DNA PCR in patients with AIDS, particularly those with low CD4 cell counts, provides additional rationale for optimization of antiretroviral therapy and consideration for preemptive anti-CMV therapy.

Adult↗

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

Model for assessment of proficiency of human immunodeficiency virus type 1 sequencing-based genotypic antiretroviral assays.

Use of sequencing-based genotyping as a diagnostic assay for human immunodeficiency virus (HIV) antiretroviral resistance is increasing. Periodic evaluation of the proficiency of laboratories performing this assay should be established. It is important to identify components of the assay that influence the generation of reliable sequencing data and that should and can be monitored. A model was developed to determine what parameters were reasonable and feasible for assessing the performance of genotyping assays. Ten laboratories using the genotyping platform, HIV-1 Genotyping System (HGS) v. 1 and software versions 1.1 or 2.0, participated in two rounds of testing. For each round, each group was sent a panel consisting of three clinical samples to sequence in real time. Six months later, seven laboratories using the TRUGENE HIV-1 Genotyping Kit participated in a separate round, working with both panels at the same time. Analysis of the data showed that one main indicator of genotyping proficiency was achievement of > or =98% sequence homology of a sample tested to a group consensus sequence for that sample. A second was concordant identification of codons at sites identified with resistance mutations in the sample, although scoring of these criteria is still undetermined from this study. These criteria are applicable to all sequence-based genotyping platforms and have been used as a baseline for assessing the performance of genotyping for the determination of antiretroviral resistance in our ongoing proficiency program.

Anti-HIV Agents↗

PubMed2004

No gender differences in the progression of nervous system disease in HIV infection.

The past decade has seen a marked increase in the number of HIV-infected women in the United States. There has been recent concern that HIV disease in general may progress more rapidly in women than men, and some studies, primarily retrospective reviews, have suggested higher rates of neurologic disease among females. The objective of this study was to assess gender differences in HIV-related central and peripheral nervous system disease over time. Participants were enrolled in a longitudinal cohort study at the University of North Carolina and had annual follow-up evaluations. At baseline, 42 HIV-negative females, 52 HIV-positive females, and 52 HIV-positive males were compared for age, education, mode of infection, absolute CD4 cell count, and plasma/cerebrospinal fluid HIV RNA load. Subjects were evaluated by standardized clinical neurologic, neuropsychological, and laboratory examinations every year. The results indicated that both HIV-positive males and HIV-positive females had poorer neurologic functioning than the control group. However, there was no evidence from the parameters measured that the rate of decline differed between HIV-positive males and HIV-positive females.

AIDS Dementia Complex↗

PubMed2004

Highly active antiretroviral therapy improves neurocognitive functioning.

Although the effects of highly active antiretroviral therapy (HAART) have resulted in substantial improvements in the systemic health of patients with HIV infection, concerns remain that these medications, which cross the blood-brain barrier poorly, may have a less beneficial effect on nervous system function. This raises the possibility that there may be a progressive long-term decline in neurologic function in patients with adequate systemic response. In a prospective longitudinal study, subjects were evaluated immediately before instituting HAART. Forty-eight subjects underwent ultrasensitive HIV RNA quantitative evaluation of both plasma and cerebrospinal fluid as well as neurologic and neuropsychological examinations. They were reevaluated 6 months after treatment initiation while receiving stable HAART. Both plasma and cerebrospinal fluid viral levels significantly declined after treatment. There was significant improvement in neurologic and neuropsychological functioning after HAART. These results indicate that despite the poor central nervous system penetration of most of these agents, there is satisfactory short-term improvement in both central nervous system viral burden and nervous system function with HAART. However, because treatment failure is increasingly likely over time, continued longitudinal evaluation of this group of subjects is required.

AIDS Dementia Complex↗

PubMed2004

Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307.

We performed a 24-week, placebo-controlled, comparative trial of hydroxyurea (HU) monotherapy, didanosine(ddI) monotherapy, and the combination of ddI plus HU administered as 1000 mg qd or 1500 mg qd in antiretroviral-naive and experienced subjects with CD4+ lymphocyte counts of 200-700 cells/mm3. Enrollment included 134 subjects. HU enhanced the antiviral activity of ddI by 1.0 log10 copies/ml after 8 weeks of therapy, with sustained responses over 24 weeks. HU alone over 4 weeks had no effect. Lamivudine resistance had little impact on antiretroviral activity when examined across treatment arms. Increases in absolute CD4+ T cell counts, but not CD4+ T cell percentages, were less in subjects who received HU compared to ddI monotherapy, and lymphoproliferative responses to antigenic and mitogenic stimuli were not altered. Subjects who received HU 1500 mg were more likely to experience dose-limiting hematological toxicities compared to those who received 1000 mg, without any additional antiviral benefit. HU may continue to have a role as a component of HIV therapy.

Anti-HIV Agents↗

PubMed2003

Short postexposure prophylaxis in newborn babies to reduce mother-to-child transmission of HIV-1: NVAZ randomised clinical trial.

BACKGROUND: In sub-Saharan Africa, most women present late for delivery with unknown HIV status, which limits the use of intrapartum nevirapine to prevent mother-to-child transmission of HIV. We aimed to determine whether post-exposure prophylaxis of nevirapine plus zidovudine given to babies only reduced transmission of HIV more than did a regimen of nevirapine alone. METHODS: We randomly assigned 1119 babies of Malawian women with HIV-1 who presented late (ie, within 2 h of expected delivery) to either nevirapine alone or nevirapine and zidovudine. Both drugs were given immediately after birth: one dose of nevirapine (2 mg/kg weight) was given as a single dose; babies in the nevirapine plus zidovudine group also received zidovudine twice daily for 1 week (4 mg/kg weight). Infant HIV infection was determined at birth and at 6-8 weeks. Primary outcome was HIV infection in babies at 6-8 weeks in those not infected at birth. Analysis was by intention to treat. FINDINGS: The overall rate of mother-to-child transmission at 6-8 weeks was 15.3% in 484 babies who received nevirapine and zidovudine and 20.9% in 468 babies who received nevirapine only (p=0.03). At 6-8 weeks, in babies who were HIV negative at birth, 34 (7.7%) babies who had nevirapine and zidovudine and 51 (12.1%) who received nevirapine only were infected (p=0.03)-a protective efficacy of 36%. This finding remained after controlling for maternal viral load and other factors at baseline. Adverse events were mild and of similar frequency in the two groups. INTERPRETATION: Postexposure prophylaxis can offer protection against HIV infection to babies of women who missed opportunities to be counselled and tested before or during pregnancy. The nevirapine and zidovudine regimen is safe and easy to implement.

Anti-HIV Agents↗

PubMed2002

Effect of HIV-1 antiretroviral prophylaxis on hepatic and hematological parameters of African infants.

OBJECTIVE: To measure hepatic and hematological parameters among neonates randomized to receive ultra-short antiretroviral regimens. DESIGN: As part of an on-going clinical trial in Malawi, infants born to women who received (early presenters) or did not receive (late presenters) standard intrapartum nevirapine (NVP) dosing were randomized to receive orally either single dose NVP alone or NVP plus zidovudine (twice daily for 1 week). An additional group of untreated infants (born to HIV-uninfected women) was enrolled as a control. METHODS: Laboratory measurements were performed at birth and repeated at 6 weeks of age. Serum alanine aminotransferase (ALT) was measured on approximately 200 infants consecutively enrolled and randomized at the start of the trial. Complete blood count (CBC) was performed on approximately 800 infants at birth and 600 infants at 6 weeks of age. ALT and CBC were also determined on approximately 200 control infants. RESULTS: At birth there were no differences in ALT values between the groups of children. At 6 weeks of age, ALT levels were significantly higher among the treated groups compared with control group (geometric mean of 11.5 U/l for controls and 16.2-19.1 U/l for treated groups; P < 0.0001). Hematological parameters did not differ between groups at birth. At 6 weeks of age, levels of hemoglobin, hematocrit, granulocytes, and platelets were significantly (P < 0.0001) lower among antiviral drug-treated groups compared with controls. These changes were consistent with grade 1 (mild) toxicity, and were more noticeable among HIV-infected infants. CONCLUSIONS: Hepatic and hematologic abnormalities associated with short-term neonatal antiretrovirals among African children are minimal.

Alanine Transaminase↗

PubMed2002

Stavudine, nevirapine and ritonavir in stable antiretroviral therapy-experienced children with human immunodeficiency virus infection.

BACKGROUND: The efficacy and tolerance of switching from zidovudine (ZDV) and lamivudine (3TC) in clinically stable HIV-infected children with incomplete viral suppression to stavudine (d4T), nevirapine (NVP) and ritonavir (RTV) has not been determined. Aim. To evaluate the safety, tolerance, antiviral activity and immunologic changes after the change to a three drug combination. METHODS: During a clinical trial in which HIV-infected antiretroviral-experienced children were initially randomized to receive d4T/RTV, ZDV/3TC/RTV or ZDV/3TC (Step 1), 48 children who had HIV RNA > or = 10,000 copies/ml after > or = 12 weeks of ZDV/3TC therapy in Step 1 were switched to d4T/NVP/RTV in Step 2. The proportion of children receiving therapy with HIV RNA < or = 400 copies/ml at Study Weeks 24 and 48 receiving d4T/NVP/RTV in Step 2 were compared with children receiving RTV-containing regimens in Step 1. RESULTS: At 24 weeks of treatment with d4T/NVP/RTV in Step 2, 48% (23 of 48) of children had HIV RNA < or = 400 copies/ml compared with 34% (31 of 92) and 47% (44 of 93) receiving d4T/RTV or ZDV/3TC/RTV for 24 weeks in Step 1; at 48 weeks virologic response was 44, 27 and 42% in Step 2 d4T/NVP/RTV, Step 1 d4T/RTV and Step 1 ZDV/3TC/RTV arms, respectively. CONCLUSIONS: A delay of 7 to 12 months in the initiation of protease inhibitor-containing combination therapy in children receiving dual nucleoside analogue therapy did not adversely affect the RNA response during the first 48 weeks of treatment.

Adolescent↗

PubMed2002

Detection of replication-competent human immunodeficiency virus type 1 (HIV-1) in cultures from patients with levels of HIV-1 RNA in plasma suppressed to less than 500 or 50 copies per milliliter.

We determined the frequency with which human immunodeficiency virus (HIV) peripheral blood mononuclear cell cultures convert from positive to negative in subjects enrolled in a substudy of AIDS Clinical Trials Group (ACTG) 320, which compared the efficacy of treatment with a combination of indinavir, zidovudine, and lamivudine (indinavir arm) to that of a combination of zidovudine and lamivudine (dual-nucleoside arm). All subjects included for study had positive baseline HIV cultures. Cultures were performed in real time with 10(7) fresh patient peripheral blood mononuclear cells, using the ACTG consensus method. We found lower rates of positive HIV cultures in the indinavir treatment arm than in the dual-nucleoside treatment arm (64 versus 96% at week 24, P < 0.001). Within the indinavir arm of the study, we found that positive cultures were less likely to occur in samples with a plasma HIV type 1 (HIV-1) RNA level of <500 copies/ml than in those with a level of >or=500 copies/ml (44 versus 90%, P < 0.001). In addition, HIV cultures from samples with HIV-1 RNA levels of >or=500 copies/ml turned positive 8.5 days earlier, on average, than those from samples with levels of <500 copies/ml (P < 0.001). However, 38% of samples with plasma RNA levels of <50 copies/ml still were positive for HIV by culture. Thus, the rates of HIV isolation by standard culture procedures decrease as the plasma viral load decreases below 1,000 copies/ml; however, HIV isolates were still obtained from a substantial proportion of subjects with RNA levels of <50 copies/ml. The delay in the time required for HIV cultures to turn positive should be considered when attempting to obtain an HIV isolate from patients with suppression of plasma viral load.

Adult↗