Biomedical subjects

James O Kahn

Publications and source records attributed to James O Kahn.

14 recordsLinked to original sources

PubMed2005

Seroconversion following nonoccupational postexposure prophylaxis against HIV.

BACKGROUND: The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP. METHODS: HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation. RESULTS: Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus. CONCLUSIONS: As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

Anti-HIV Agents↗

PubMed2004

Interleukin-2 therapy restores CD8 cell non-cytotoxic anti-HIV responses in primary infection subjects receiving HAART.

OBJECTIVE: To determine the effect of interleukin-2 (IL-2) therapy on immunologic and virologic responses in subjects with acute or recent HIV infection already receiving highly active antiretroviral therapy (HAART). METHODS: The effect of IL-2 therapy on immunologic and virologic responses was studied in 21 acutely infected individuals who had been receiving HAART for 48 weeks following acute or recent HIV infection. Nine subjects receiving no therapy served as controls. Viral loads, as well as CD4 and CD8 cell counts were monitored and the CD8 cell non-cytotoxic anti-HIV response (CNAR) was measured. RESULTS: IL-2 therapy led to significant increases in CD4 cell numbers (P = 0.005) that were maintained for 6 months after discontinuation of the IL-2 treatment. No effect of IL-2 was observed on viral loads or the CD8 cell numbers as compared to subjects receiving HAART alone. CNAR activity was restored among subjects receiving HAART and IL-2 whereas CNAR declined among those receiving HAART alone and in untreated infected subjects. The percentage of HAART subjects with CD8 cells showing at least 50% suppression of HIV replication increased significantly following IL-2 therapy (P = 0.02) and persisted for 6 months. CONCLUSIONS: In primary HIV infection administering IL-2 concomitant with HAART following 1 year of treatment with HAART gives a significant increase in CD4 cells and a previously unrecognized beneficial effect on the CD8 cell non-cytotoxic anti-HIV response.

Acute Disease↗

PubMed2004

Cost-effectiveness of HIV postexposure prophylaxis following sexual or injection drug exposure in 96 metropolitan areas in the United States.

OBJECTIVES: To evaluate the cost-effectiveness of HIV postexposure prophylaxis (PEP) following sexual or injection-related exposures in 96 metropolitan statistical areas in the United States (MSA). DESIGN: Empirical, model-based cost-effectiveness analysis. METHODS: Epidemiological and population size estimates from the literature were combined with information about the distribution of exposure types, PEP completion rate, proportion of source partners known to be HIV infected, and PEP program costs obtained from a feasibility study of PEP in San Francisco to estimate the cost-effectiveness of hypothetical PEP programs in each of the 96 MSA. The effectiveness of combination antiretroviral therapy following sexual or drug use-related exposures, which is presently not known, was assumed equal to the effectiveness of zidovudine monotherapy in the occupational setting. The main outcome measure was the cost-utility ratio, defined as the cost per quality-adjusted life year (QALY) saved by the PEP intervention. RESULTS: The cost-utility ratios for the 96 MSA ranged from 4137 dollars to 39,101 dollars per QALY saved; only two of the ratios exceeded 30,000 dollars per QALY saved. Combined across the 96 MSA, the hypothetical PEP programs would reach nearly 20,000 clients at a total cost of approximately 22 million dollars. The overall cost-utility ratio across MSA was 12,567 dollars per QALY saved. The majority of the HIV infections prevented by PEP were among men and women who reported receptive anal intercourse exposure. CONCLUSIONS: PEP following sexual or drug use-related exposures could be a cost-effective complement to existing HIV-prevention efforts in most MSA across the United States.

Chemoprevention↗

PubMed2004

HIV RNA testing in the context of nonoccupational postexposure prophylaxis.

BACKGROUND: The specificity and positive predictive value of human immunodeficiency virus (HIV) RNA assays have not been evaluated in the setting of postexposure prophylaxis (PEP). METHODS: Plasma from subjects enrolled in a nonoccupational PEP study was tested with 2 branched-chain DNA (bDNA) assays, 2 polymerase chain reaction (PCR) assays, and a transcription-mediated amplification (TMA) assay. Assay specificity and positive predictive value were determined for subjects who remained negative for HIV antibody for >or=3 months. RESULTS: In 329 subjects examined, the lowest specificities (90.1%-93.7%) were seen for bDNA testing performed in real time. The highest specificities were seen with batched bDNA version 3.0 (99.1%), standard PCR (99.4%), ultrasensitive PCR (100%), and TMA (99.6%) testing. Only the 2 assays with the highest specificities had positive predictive values >40%. For the bDNA assays, increasing the cutoff point at which a test is called positive (e.g., from 50 copies/mL to 500 copies/mL for version 3.0) increased both specificity and positive predictive values to 100%. CONCLUSIONS: The positive predictive value of HIV RNA assays in individuals presenting for PEP is unacceptably low for bDNA-based testing and possibly acceptable for PCR- and TMA-based testing. Routine use of HIV RNA assays in such individuals is not recommended.

Anti-HIV Agents↗

PubMed2004

Higher CD4+ T cell counts associated with low viral pol replication capacity among treatment-naive adults in early HIV-1 infection.

BACKGROUND: Infection with primary drug-resistant human immunodeficiency virus type 1 (HIV-1) has been associated with higher CD4(+) T cell counts in drug-naive patients, suggesting that altered viral pol replication capacity (RC) associated with drug resistance diminishes immune injury in vivo, independent of exposure to drugs. METHODS: Virus replication over a single cycle was measured by use of a viral test vector containing patient-derived HIV-1 protease and reverse transcriptase gene segments. RESULTS: Among 191 recently infected patients, pol RC ranged widely, with only 6% of the variance explained by drug-resistance mutations. Patients infected with a virus with a low pol RC (</=43% of the reference virus) had significantly higher CD4(+) T cell counts at study entry, independent of drug resistance and plasma HIV-1 RNA level, and over time, both before and during combination antiretroviral therapy. CONCLUSIONS: Viral pol RC may influence HIV-1 disease progression by affecting the amount and tissue distribution of viral replication. The pol RC value of 43% may represent a threshold below which HIV-1 has lowered virulence and is less able to deplete CD4(+) T cell counts.

Adult↗

PubMed2004

Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load.

Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation "set point" is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10,000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.

Adult↗

PubMed2004

Use of postexposure prophylaxis against HIV infection following sexual exposure does not lead to increases in high-risk behavior.

BACKGROUND: The effectiveness of postexposure prophylaxis (PEP) following occupational exposure to HIV has prompted advocacy for PEP following sexual or drug-use exposures. OBJECTIVE: To evaluate the concern that the availability of PEP for sexual or drug-use exposures might result in behavioral disinhibition. DESIGN: Non-randomized trial of 397 adults with high-risk sexual or drug-use exposures within the prior 72 h. INTERVENTIONS: Antiretroviral medication for 4 weeks and five counseling sessions. MAIN OUTCOME MEASUREMENTS: Participants were followed for 12 months for repeat request for PEP and for changes compared with pre-enrollment in overall high-risk behavior and the acquisition of sexually transmitted diseases (STD) and HIV. RESULTS: After 12 months following receipt of PEP, the majority of participants (83%) did not request a repeat course of PEP. At 12 months after exposure, 73% of participants reported a decrease compared with baseline in the number of times they had performed high-risk sexual acts; 13% reported no change, and 14% had an increase. Most participants (85%) had no change in the incidence of STD; 8.5% had a decrease and 6.8% an increase. Three homosexual men seroconverted for HIV (none associated with the presenting exposure) for a rate of 1.2/100 person-year, equivalent to rates in San Francisco among all homosexual men. CONCLUSIONS: After receipt of PEP consisting of antiretroviral medication and behavioral counseling following a potential sexual exposure to HIV, most individuals do not increase high-risk behavior. Coupled with prior safety and feasibility data, this lack of behavioral disinhibition suggests that use of PEP should be routinely considered following high-risk sexual exposures.

Adult↗

PubMed2004

Cost-effectiveness of postexposure prophylaxis after sexual or injection-drug exposure to human immunodeficiency virus.

BACKGROUND: The cost-effectiveness of interventions that provide human immunodeficiency virus (HIV) postexposure prophylaxis (PEP) to individuals after sexual or injection-drug use exposures depends on the distribution of exposure routes, prevalence of infection among source partners, adherence to PEP regimens, medical care costs, and prevailing epidemiologic contexts, among other factors. OBJECTIVE: To determine the cost-effectiveness of a comprehensive program to prevent HIV infection after sexual or injection-drug use exposure for 401 persons seeking PEP in an urban community. METHODS: We conducted a retrospective cost analysis to evaluate the cost of the PEP intervention, then combined this information with model-based effectiveness estimates to determine the PEP program's "cost-utility ratio," which is the ratio of net program costs to the total number of quality-adjusted life-years (QALYs) saved by the program. RESULTS: The average cost of the PEP regimen was $1222, and the total cost of the program was $450 970. The PEP program prevented an estimated 1.26 HIV infections, saved 11.74 QALYs, and averted $281 323 in future HIV-related medical care costs. The overall cost-utility ratio was $14 449 per QALY saved. When analysis was restricted to men reporting receptive anal intercourse, the savings in averted HIV-related medical care costs exceeded the cost of the program. The results were generally robust to changes in key parameter values but were sensitive to assumptions about the HIV transmission probability for receptive anal intercourse. CONCLUSIONS: For this study population, HIV PEP was cost-effective by conventional standards and cost-saving for persons seeking PEP after male-male receptive anal intercourse.

Anti-HIV Agents↗

PubMed2003

Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection.

BACKGROUND: HLA-B57, as well as cytotoxic T-lymphocyte (CTL) responses restricted by this allele, have been strongly associated with long-term non-progressive chronic HIV-1 infection. However, their impact on viral replication during acute HIV-1 infection is not known. METHODS: Clinical and immunological parameters during acute and early HIV-1 infection in individuals expressing HLA-B57 were assessed. HIV-1-specific T-cell responses were determined by peptide-specific interferon-gamma production measured using Elispot assay and flow-based intracellular cytokine quantification. RESULTS: Individuals expressing HLA-B57 presented significantly less frequently with symptomatic acute HIV-1 infection (4/116, 3.4%) than expected from the frequency of chronically infected individuals expressing this allele (43/446, 9.6%; P < 0.05). During acute infection, virus-specific CD8 T-cell responses were dominated by HLA-B57-restricted responses, with significantly broader (P < 0.02) and stronger (P < 0.03) responses restricted by HLA-B57 than restricted by all other co-expressed HLA class I alleles combined. Six out of nine individuals expressing HLA-B57 controlled HIV-1 viremia in the absence of therapy at levels < 5000 copies/ml (median, 515 copies/ml) during up to 29 months following acute infection. CONCLUSION: These data demonstrate that host genetic factors can influence the clinical manifestations of acute HIV-1 infection and provide a functional link between HLA-B57 and viral immune control.

Acute Disease↗

PubMed2003

Greater reversal of CD4+ cell abnormalities and viral load reduction after initiation of antiretroviral therapy with zidovudine, lamivudine, and nelfinavir before complete HIV type 1 seroconversion.

In a prospective open-label study, 41 male subjects received nelfinavir, zidovudine, and lamivudine stratified as either: early stage (ES; negative/indeterminate Western blot; n = 19) or late stage (LS; positive Western blot; n = 22) primary HIV-1 infection. Despite higher median baseline HIV-1 RNA levels and lower CD4(+) cell numbers in the ES subjects, a significantly greater decline in viral load (-3.46 vs. -2.83 log(10) copies/ml; p = 0.023) and increase in CD4(+) cell number (+85 vs. +41 cells/month increase, p = 0.01) were observed over the first 3 months of therapy such that both groups had comparable results at 1 year. The proportion with HIV-1 RNA < 50 copies/mL at 1 year was similar (9 of 19 ES subjects and 11 of 22 LS subjects by intention-to-treat analysis). Memory CD4(+) cell numbers, and activated CD4(+) percentages, were also significantly improved in ES subjects. Despite poorer prognostic markers at baseline ES subjects achieved responses similar to those of LS subjects after 1 year of treatment.

Anti-HIV Agents↗

PubMed2002

Time trends in primary HIV-1 drug resistance among recently infected persons.

CONTEXT: Transmission of multiclass drug-resistant human immunodeficiency virus type 1 (HIV-1) may increase with wider use of antiretroviral therapy. OBJECTIVE: To determine trends in prevalence of HIV-1 drug resistance among recently infected individuals in a geographic area with a high penetration of antiviral treatment. DESIGN, SETTING, AND PATIENTS: Consecutive case series of 225 patients referred to a San Francisco, Calif, hospital with recent HIV-1 infection from June 1996 through June 2001. MAIN OUTCOME MEASURE: Time trends in the prevalence of genotypic and phenotypic primary drug resistance. RESULTS: Mutations associated with resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) steadily increased from 0% in 1996-1997 to 12 (13.2%) in 2000-2001 (P =.01). There was 1 mutation associated with protease inhibitor resistance in 1996-1997 (2.5%) and there were 7 (7.7%) in 2000-2001 (P =.25). Genotypic resistance to nucleoside reverse transcriptase inhibitors (NRTIs) initially decreased and then returned to prior levels (P =.007 for test of homogeneity). Genotypic resistance to 2 or more classes of drugs increased from 1 (2.5%) to 12 (13.2%) (P =.004), but only 1 infection (1.2%) in the latter period was resistant to all 3 classes of agents (P =.58). Primary phenotypic resistance decreased for NRTIs from 21% to 6.2% (P =.03) and increased for NNRTIs from 0 to 8 (9.9%) (P =.02). Phenotypic resistance increased for protease inhibitors from 2.6% to 6.2% (P =.32). Median time to virologic suppression (<500 copies/mL) during therapy was 12 weeks for patients with genotypic evidence of resistance compared with 5 weeks for patients with drug-sensitive infections (P =.02). CONCLUSIONS: The frequency of primary resistance to NNRTIs is increasing, although resistance to all available classes of antiretroviral therapy remains rare. Genotypic resistance testing in recently infected persons predicts time to viral suppression during therapy.

Adult↗

PubMed2002

Increased HLA-DR expression on peripheral blood monocytes in subsets of subjects with primary HIV infection is associated with elevated CD4 T-cell apoptosis and CD4 T-cell depletion.

Whereas T-cell activation parameters of HIV disease have been extensively studied, the activation status of circulating monocytes has received less attention. Sixty-one subjects with primary HIV infection were evaluated by fluorescent-activated cell sorter (FACS) analysis at baseline (pretreatment) for CD4 T-cell count, CD4 T-cell apoptosis, and immune activation. A subset of 15 subjects with marked elevated (3 standard deviations above normal) monocyte DR expression had significantly reduced CD4 T-cell counts at baseline (p <.01) when compared with 46 subjects without monocyte activation. Ten subjects who presented with elevated levels of both CD14/DR, and CD4/CD38, had higher CD4 T-cell apoptosis (p <.001), and lower CD4 T-cell counts (p <.001) and higher baseline plasma HIV RNA (p <.01) than 21 subjects without elevated CD14/DR and CD4/CD38 coexpression. Fifty subjects were subsequently evaluated for immune cell activation over 24 weeks postinitiation of highly active antiretroviral therapy (HAART). A subgroup of 5 subjects who had persistent CD14/DR activation showed continuous depression of CD4 T-cell counts persisting for up to 2 years. The CD4 T-cell counts of this subgroup were significantly lower, at all time points, in comparison to 35 subjects who lacked any persistent expression of monocyte or CD4 T-cell activation (at 24 weeks, p <.002). We conclude that monocyte activation as defined by elevation of CD14/DR expression correlates to CD4 T-cell depletion in primary HIV infection, and is predictive of a poor CD4 T-cell response to HAART in a subset of patients.

ADP-ribosyl Cyclase↗

PubMed2002

Use of laboratory tests and clinical symptoms for identification of primary HIV infection.

OBJECTIVE: To determine the sensitivity and specificity of symptoms, three HIV-1 RNA assays, a p24 antigen EIA and a third-generation enzyme immunoassay (EIA) antibody test for diagnosis of primary HIV infection (PHI). DESIGN: Prospective cohort in a university research program. PARTICIPANTS: Of 258 eligible persons screened for PHI, 40 had primary/early infection (22 preseroconversion, 18 within 6 months of seroconversion) and 218 did not. Seven participants with preseroconversion HIV-1 from a second center were added for evaluating laboratory tests. MAIN OUTCOME MEASURE: PHI, defined as a negative or indeterminate antibody test with subsequent conversion. Symptom analysis also included persons with antibody conversion of less than 6 months' duration. RESULTS: The symptoms most strongly associated with PHI in multivariate analysis were fever [odds ratio (OR) 5.2; 95% confidence interval (CI) 2.3-11.7] and rash (OR 4.8; 95% CI 2.4-9.8). The sensitivity and specificity, respectively, for detecting preseroconversion HIV infection were: p24 antigen, 79% and 99%; third-generation EIA, 79% and 97%; HIV-1 RNA by branched chain DNA 100% and 95%; HIV-1 RNA by polymerase chain reaction 100% and 97%; HIV-1 RNA by transcription-mediated amplification testing, 100% and 98%. False-positive HIV-1 RNA tests were not reproducible and had values < 3000 copies/ml, while only one person with confirmed PHI was in this range. CONCLUSIONS: Rash and fever indicated the highest risk of PHI. HIV-1 RNA tests are very sensitive for PHI but false-positive results occur. False-positive results can be reduced through duplicate testing and considering tests < 5000 copies/ml as indeterminate results requiring additional testing. p24 antigen was more specific than HIV-1 RNA testing but less sensitive.

Adult↗

PubMed2002

Development of WF10, a novel macrophage-regulating agent.

WF10 represents a new class of drug involved in regulating macrophage function both in vitro and in vivo. In the US, WF10 is being evaluated in patients with advanced HIV infection as an adjunct to highly active antiretroviral therapy (HAART). To date, most therapeutic efforts to treat HIV infection have focused on inhibition of viral replication with the goal of decreasing viral load. The introduction of HAART was associated with a dramatic decline in AIDS-related mortality; however, recent indications suggest that the trend maybe changing. WF10, which contains chlorite as the active principle, causes profound changes in macrophage function and activation of gene expression, and appears to downregulate inappropriate immunological activation. The loss of T-cell function observed in HIV-infected patients likely requires the involvement of chronically activated macrophages. Therefore, the persistently activated macrophage represents a therapeutic target that is, unlike HIV, not highly mutable. With this target as a focus, WF10 is being developed for use in advanced HIV disease. WF10 is currently being studied in the US, Europe and Asia for treatment of late-stage HIV disease, as well as recurrent prostate cancer, late post-radiation cystitis, autoimmune disease and chronic active hepatitis C disease.

Chlorine↗