Bio

Academic Appointments


Administrative Appointments


  • Chief of the Medical Service, VA Palo Alto Health Care System (2012 - Present)

Honors & Awards


  • Charles C. Shepard Science Award for Scientific Excellence, Centers for Disease Control and Prevention (1999)
  • Outstanding Mentor, University of California, San Francisco, AIDS Research Institute (2008)

Professional Education


  • AB, University of California, Berkeley, American History (1978)
  • MD, University of California, San Francisco, Medicine (1982)
  • Intern, Johns Hopkins Hospital--Osler Service, Medicine (1983)
  • Resident, Johns Hopkins Hospital--Osler Service, Medicine (1984)
  • Resident, University of California, San Francisco, Medicine, Primary Care (1985)
  • Fellow, University of California, San Francisco, Medical Oncology (1987)

Research & Scholarship

Current Research and Scholarly Interests


My initial research activities have focused on three areas: antiretroviral and novel therapeutic treatments of HIV infection, understanding elements of HIV pathogenesis associated with acute HIV infection and post exposure prevention. My most recent scholarly activities concentrate on working as a team to capitalize on the data stored in electronic medical records, HIV disease modeling and using electronic medical records for outcome research and developing a mentorship program for doctoral, post-doctoral scholars and early career faculty dedicated to translational and clinical research. I have experience as the national chair for an NIAID sponsored AIDS Clinical Trials Group study and I have conducted Phase 1 through Phase 3 studies. My scholarship has been supported by funding from the NIH for 24 years through a variety of mechanisms including, as the principal investigator of R01, R18, R24, R35 and K24 grants and co-investigator for R01, R18, R24 and R33 awards. Three foundations have supported my scholarly activities: the California Healthcare Foundation, the Blue Shield Foundation and the Commonwealth Foundation and I have received three career awards, one from the American Cancer Society and two K24 awards from the NIH (NIMH and NCRR).

Teaching

Graduate and Fellowship Programs


Publications

Journal Articles


  • Next: Text JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Kahn, J. S. 2012; 307 (17): 1807-1808

    View details for Web of Science ID 000303386800019

    View details for PubMedID 22550195

  • A Cross-Sectional Study of Barriers to Personal Health Record Use among Patients Attending a Safety-Net Clinic PLOS ONE Hilton, J. F., Barkoff, L., Chang, O., Halperin, L., Ratanawongsa, N., Sarkar, U., Leykin, Y., Munoz, R. F., Thom, D. H., Kahn, J. S. 2012; 7 (2)

    Abstract

    Personal health records (PHR) may improve patients' health by providing access to and context for health information. Among patients receiving care at a safety-net HIV/AIDS clinic, we examined the hypothesis that a mental health (MH) or substance use (SU) condition represents a barrier to engagement with web-based health information, as measured by consent to participate in a trial that provided access to personal (PHR) or general (non-PHR) health information portals and by completion of baseline study surveys posted there.Participants were individually trained to access and navigate individualized online accounts and to complete study surveys. In response to need, during accrual months 4 to 12 we enhanced participant training to encourage survey completion with the help of staff. Using logistic regression models, we estimated odds ratios for study participation and for survey completion by combined MH/SU status, adjusted for levels of computer competency, on-study training, and demographics.Among 2,871 clinic patients, 70% had MH/SU conditions, with depression (38%) and methamphetamine use (17%) most commonly documented. Middle-aged patients and those with a MH/SU condition were over-represented among study participants (N?=?338). Survey completion was statistically independent of MH/SU status (OR, 1.85 [95% CI, 0.93-3.66]) but tended to be higher among those with MH/SU conditions. Completion rates were low among beginner computer users, regardless of training level (<50%), but adequate among advanced users (>70%).Among patients attending a safety-net clinic, MH/SU conditions were not barriers to engagement with web-based health information. Instead, level of computer competency was useful for identifying individuals requiring substantial computer training in order to fully participate in the study. Intensive on-study training was insufficient to enable beginner computer users to complete study surveys.

    View details for DOI 10.1371/journal.pone.0031888

    View details for Web of Science ID 000302871500097

    View details for PubMedID 22363761

  • Personal health records in a public hospital: experience at the HIV/AIDS clinic at San Francisco General Hospital. J Am Med Inform Assoc Kahn JS, Hilton JF, Van Nunnery T, Leasure S, Bryant KM, Hare CB, Thom DH 2010; 17 (2): 224-8
  • Evolutionary dynamics of complex networks of HIV drug-resistant strains: the case of San Francisco. Science Smith RJ, Okano JT, Kahn JS, Bodine EN, Blower S 2010; 327 (5966): 697-701
  • Evidence for risk-stratification when monitoring for toxicities following initiation of combination antiretroviral therapy. AIDS (London, England) Taiwo, B., Yanik, E. L., Napravnik, S., Ryscavage, P., Koletar, S. L., Moore, R., Mathews, W. C., Crane, H. M., Mayerr, K., Zinski, A., Kahn, J. S., Eron, J. J. 2013

    Abstract

    OBJECTIVE:: Laboratory monitoring is recommended during combination antiretroviral therapy (cART), but the pattern of detected abnormalities and optimal monitoring are unknown. We assessed laboratory abnormalities during initial cART in 2000-2010 across the United States. DESIGN:: Observational study in the Centers for AIDS Research Network of Integrated Clinical Systems Cohort METHODS:: Among patients with normal results within a year prior to cART initiation, time to first significant abnormality was assessed by Kaplan-Meier curves stratified by event type, with censoring at first of regimen change, loss to follow-up, or 104 weeks. Incidence rates of first events were estimated using Poisson regression; multivariable analyses identified associated factors. Results were stratified by time (16 weeks) from therapy initiation. RESULTS:: 3,470 individuals contributed 3,639 person-years. Median age, pre-cART CD4 and follow-up duration were 40 years, 206?cells/mm and 51 weeks, respectively. Incidence rates for significant abnormalities (per 100 person-years) in the first 16 weeks post cART initiation were: lipid?=?49 (95% Confidence Interval [CI]: 41-58); hematologic?=?44 (40-49); hepatic?=?24 (20-27); and renal?=?9 (7-11), dropping substantially during weeks 17-104 of cART to lipid?=?23 (18-29); hematologic?=?5 (4-6); hepatic?=?6 (5-8); and renal?=?2 (1-3) (all p?

    View details for PubMedID 23435300

  • Characterizing HIV Transmission Networks Across the United States CLINICAL INFECTIOUS DISEASES Aldous, J. L., Pond, S. K., Poon, A., Jain, S., Qin, H., Kahn, J. S., Kitahata, M., Rodriguez, B., Dennis, A. M., Boswell, S. L., Haubrich, R., Smith, D. M. 2012; 55 (8): 1135-1143

    Abstract

    Clinically, human immunodeficiency virus type 1 (HIV-1) pol sequences are used to evaluate for drug resistance. These data can also be used to evaluate transmission networks and help describe factors associated with transmission risk.HIV-1 pol sequences from participants at 5 sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort from 2000-2009 were analyzed for genetic relatedness. Only the first available sequence per participant was included. Inferred transmission networks ("clusters") were defined as ?2 sequences with ?1.5% genetic distance. Clusters including ?3 patients ("networks") were evaluated for clinical and demographic associations.Of 3697 sequences, 24% fell into inferred clusters: 155 clusters of 2 individuals ("dyads"), 54 clusters that included 3-14 individuals ("networks"), and 1 large cluster that included 336 individuals across all study sites. In multivariable analyses, factors associated with being in a cluster included not using antiretroviral (ARV) drugs at time of sampling (P < .001), sequence collected after 2004 (P < .001), CD4 cell count >350 cells/mL (P < .01), and viral load 10,000-100,000 copies/mL (P < .001) or >100,000 copies/mL (P < .001). In networks, women were more likely to cluster with other women (P < .001), and African Americans with other African Americans (P < .001).Molecular epidemiology can be applied to study HIV transmission networks in geographically and demographically diverse cohorts. Clustering was associated with lack of ARV use and higher viral load, implying transmission may be interrupted by earlier diagnosis and treatment. Observed female and African American networks reinforce the importance of diagnosis and prevention efforts targeted by sex and race.

    View details for DOI 10.1093/cid/cis612

    View details for Web of Science ID 000309070500021

    View details for PubMedID 22784872

  • A Mentor Development Program for Clinical Translational Science Faculty Leads to Sustained, Improved Confidence in Mentoring Skills CTS-CLINICAL AND TRANSLATIONAL SCIENCE Feldman, M. D., Steinauer, J. E., Khalili, M., Huang, L., Kahn, J. S., Lee, K. A., Creasman, J., Brown, J. S. 2012; 5 (4): 362-367

    Abstract

    Mentorship is crucial for academic productivity and advancement for clinical and translational (CT) science faculty. However, little is known about the long-term effects of mentor training programs. The University of California, San Francisco (UCSF), Clinical and Translational Science Institute launched a Mentor Development Program (MDP) in 2007 for CT faculty. We report on an evaluation of the first three cohorts of graduates from the MDP. In 2010, all Mentors in Training (MITs) who completed the MDP from 2007 to 2009 (n= 38) were asked to complete an evaluation of their mentoring skills and knowledge; all MITs (100%) completed the evaluation. Two-thirds of MDP graduates reported that they often apply knowledge, attitudes, or skills obtained in the MDP to their mentoring. Nearly all graduates (97%) considered being a mentor important to their career satisfaction. Graduates were also asked about the MDP's impact on specific mentoring skills; 95% agreed that the MDP helped them to become a better mentor and to focus their mentoring goals. We also describe a number of new initiatives to support mentoring at UCSF that have evolved from the MDP. To our knowledge, this is the first evaluation of the long-term impact of a mentor training program for CT researchers.

    View details for DOI 10.1111/j.1752-8062.2012.00419.x

    View details for Web of Science ID 000307382000015

    View details for PubMedID 22883616

  • Modeling dynamic interactions between pre-exposure prophylaxis interventions & treatment programs: predicting HIV transmission & resistance SCIENTIFIC REPORTS Supervie, V., Barrett, M., Kahn, J. S., Musuka, G., Moeti, T. L., Busang, L., Blower, S. 2011; 1

    Abstract

    Clinical trials have recently demonstrated the effectiveness of Pre-Exposure Prophylaxis (PrEP) in preventing HIV infection. Consequently, PrEP may soon be used for epidemic control. We model the dynamic interactions that will occur between treatment programs and potential PrEP interventions in resource-constrained countries. We determine the consequences for HIV transmission and drug resistance. We use response hypersurface modeling to predict the effect of PrEP on decreasing transmission as a function of effectiveness, adherence and coverage. We predict PrEP will increase need for second-line therapies (SLT) for treatment-naïve individuals, but could significantly decrease need for SLT for treatment-experienced individuals. If the rollout of PrEP is carefully planned it could increase the sustainability of treatment programs. If not, need for SLT could increase and the sustainability of treatment programs could be compromised. Our results show the optimal strategy for rolling out PrEP in resource-constrained countries is to begin around the "worst" treatment programs.

    View details for DOI 10.1038/srep00185

    View details for Web of Science ID 000300563900002

    View details for PubMedID 22355700

  • Transmitted Drug Resistance in the CFAR Network of Integrated Clinical Systems Cohort: Prevalence and Effects on Pre-Therapy CD4 and Viral Load PLoS Med Poon A, Frost S, Aldous J, Mathews W, Kitahata M, Rodriguez B, Saag M, Boswell S, Kahn J, Haubrich R 2011; 6 (6): e21189
  • Mortality Among Antiretroviral-Eligible Patients in an Urban Public Clinic J Acquir Immune Defic Syndr Dowdy DW, Geng EH, Christopoulos KA, Kahn JS, Hare CB, Wlodarczyk D, Havlir DV 2011; 57 (4): 297-300
  • A Randomized Noninferiority Trial of Standard Versus Enhanced Risk Reduction and Adherence Counseling for Individuals Receiving Post-Exposure Prophylaxis Following Sexual Exposures to HIV Clin Infect Dis Roland ME, Neilands TB, Krone MR, Coates TJ, Franses K, Chesney MA, Kahn JS, Martin JN. 2011; 53 (1): 76-83
  • The effect of AIDS Clinical Trials Group Protocol 5164 on the time from Pneumocystis jirovecii pneumonia diagnosis to antiretroviral initiation in routine clinical practice: a case study of diffusion, dissemination, and implementation. Clin Infect Dis Geng EH, Kahn JS, Chang OC, Hare CB, Christopoulos KA, Jones D, Petersen ML, Deeks SG, Havlir DV, Gandhi M 2011; 53 (10): 1008-14
  • Should we try to eliminate HIV epidemics by using a 'Test and Treat' strategy? AIDS Wagner BG, Kahn JS, Blower S 2010; 13 (24): 775-6
  • The potential roles of mHealth in developing economies: Can they be realized? Health Affairs Kahn JG, Yang J, Kahn JS 2010; 29 (2): 254-61
  • Training the next generation of research mentors: the University of California, San Francisco, Clinical & Translational Science Institute Mentor Development Program. Clin Transl Sci Feldman MD, Huang L, Guglielmo BJ, Jordan R, Kahn J, Creasman JM, Wiener-Kronish JP, Lee KA, Tehrani A, Yaffe K, Brown JS 2009; 2 (3): 216-21
  • Quantifying the treatment efficacy of reverse transcriptase inhibitors: new analyses of clinical data based on within-host modeling. BMC Public Health Breban R, Napravnik S, Kahn J, Blower S 2009; 9 (Suppl 1): 11
  • Mentoring early-career scientists for HIV research careers Am J Public Health Kahn JS, Greenblatt RM 2009; 99 (1 Suppl): S37-42
  • What it takes: characteristics of the ideal personal health record Health Affairs Kahn JS, Aulakh V, Bosworth A 2009; 28 (2): 369-76
  • Cohort profile: The Centers for AIDS Research Network of Integrated Clinical Systems INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Kitahata, M. M., Rodriguez, B., Haubrich, R., Boswell, S., Mathews, W. C., Lederman, M. M., Lober, W. B., Van Rompaey, S. E., Crane, H. M., Moore, R. D., Bertram, M., Kahn, J. O., Saag, M. S. 2008; 37 (5): 948-955

    View details for DOI 10.1093/ije/dym231

    View details for Web of Science ID 000259771500009

    View details for PubMedID 18263650

  • Mentoring the next generation of HIV prevention researchers - A model mentoring program at the University of California San Francisco and Gladstone Institute of Immunology and Virology Center for AIDS research JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Kahn, J., Jarlais, C. D., Dobkin, L., Barrs, S. F., Greenblatt, R. M. 2008; 47: S5-S9

    Abstract

    Mentoring is critical to develop and nurture early career investigators, helping them to succeed in building networks of colleagues, and is especially important for investigators focused on HIV research. We piloted a multidiscipline mentoring program targeting postdoctoral scholars and early career faculty concentrating on HIV/AIDS research.The pilot mentoring program was conducted at the Center for AIDS Research (CFAR) at the University of California San Francisco and the Gladstone Institute of Virology and Immunology. Mentees were self-referred postdoctoral scholars and early career faculty. Mentors were drawn from the senior faculty. Early career mentees were matched with senior investigators for individual meetings, a monthly workshop on topics directed by the mentees, and single-day mentoring seminars.More than 30 mentees and 20 mentors have participated in the pilot project. Most mentees reported that the 1-on-1 mentoring was a satisfying experience. The most highly valued activities were those that facilitated networking among mentees, networking between mentors and mentees, and workshops that focused on grant applications and first academic appointments and promotions.A multidisciplinary mentoring program for postdoctoral scholars and early career faculty focused on HIV/AIDS research is valuable. Umbrella organizations, such as the CFAR, are well suited to create and provide highly valued mentoring experiences.

    View details for Web of Science ID 000253821200002

    View details for PubMedID 18301135

  • Signposts along the NIH roadmap for reengineering clinical research: lessons from the Clinical Research Networks initiative Arch Intern Med Williams RL, Johnson SB, Greene SM, Larson EB, Green LA, Morris A, Confer D, Reaman G, Madigan R, Kahn J; Principal Investigators of Clinical Research Networks Initiative 2008; 168 (17): 1919-25
  • Human immunodeficiency virus type 1 Vpr induces DNA replication stress in vitro and in vivo. J Virol Zimmerman ES, Sherman MP, Blackett JL, Neidleman JA, Kreis C, Mundt P, Williams SA, Warmerdam M, Kahn J, Hecht FM, Grant RM, de Noronha CM, Weyrich AS, Greene WC, Planelles V 2006; 80 (21): 10407-18
  • Excellent safety and tolerability of the human immunodeficiency virus type 1 pGA2/JS2 plasmid DNA priming vector vaccine in HIV type 1 uninfected adults. AIDS Res Hum Retroviruses Mulligan MJ, Russell ND, Celum C, Kahn J, Noonan E, Montefiori DC, Ferrari G, Weinhold KJ, Smith JM, Amara RR, Robinson HL; NIH/NIAID/DAIDS HIV Vaccine Trials Network. 2006; 22 (7): 678-83
  • Predicting the epidemiological impact of antiretroviral allocation strategies in KwaZulu-Natal: the effect of the urban-rural divide. Proc Natl Acad Sci USA Wilson DP, Kahn J, Blower SM 2006; 103 (38): 14228-33
  • Seroconversion following nonoccupational postexposure prophylaxis against HIV CLINICAL INFECTIOUS DISEASES Roland, M. E., Neilands, T. B., Krone, M. R., Katz, M. H., Franses, K., Grant, R. M., Busch, M. P., Hecht, F. M., Shacklett, B. L., Kahn, J. O., Bamberger, J. D., Coates, T. J., Chesney, M. A., Martin, J. N. 2005; 41 (10): 1507-1513

    Abstract

    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.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.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.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.

    View details for Web of Science ID 000232670400018

    View details for PubMedID 16231265

  • The antiretroviral rollout & drug resistant HIV in Africa: insights from empirical data & theoretical models. AIDS Res Hum Retroviruses Blower S, Bondine E, Kahn J, McFarland W 2005; 19 (1): 1-14
  • Cost-effectiveness of HIV postexposure prophylaxis following sexual or injection drug exposure in 96 metropolitan areas in the United States AIDS Pinkerton, S. D., Martin, J. N., Roland, M. E., Katz, M. H., Coates, T., Kahn, J. O. 2004; 18 (15): 2065-2073

    Abstract

    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).Empirical, model-based cost-effectiveness analysis.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.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.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.

    View details for Web of Science ID 000225225800011

    View details for PubMedID 15577628

  • Interleukin-2 therapy restores CD8 cell non-cytotoxic anti-HIV responses in primary infection subjects receiving HAART AIDS Martinez-Marino, B., Shiboski, S., Hecht, F. M., Kahn, J. O., Levy, J. A. 2004; 18 (15): 1991-1999

    Abstract

    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).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.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.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.

    View details for Web of Science ID 000225225800003

    View details for PubMedID 15577620

  • Immune activation set point during early FHV infection predicts subsequent CD4(+) T-cell changes independent of viral load BLOOD Deeks, S. G., Kitchen, C. M., Liu, L., Guo, H., Gascon, R., Narvaez, A. B., Hunt, P., Martin, J. N., Kahn, J. O., Levy, J., McGrath, M. S., Hecht, F. M. 2004; 104 (4): 942-947

    Abstract

    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.

    View details for DOI 10.1182/blood-2003-09-3333

    View details for Web of Science ID 000223145800014

    View details for PubMedID 15117761

  • HIV RNA testing in the context of nonoccupational postexposure prophylaxis JOURNAL OF INFECTIOUS DISEASES Roland, M. E., Elbeik, T. A., Kahn, J. O., Bamberger, J. D., Coates, T. J., Krone, M. R., Katz, M. H., Busch, M. P., Martin, J. N. 2004; 190 (3): 598-604

    Abstract

    The specificity and positive predictive value of human immunodeficiency virus (HIV) RNA assays have not been evaluated in the setting of postexposure prophylaxis (PEP).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.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%.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.

    View details for Web of Science ID 000222549500025

    View details for PubMedID 15243937

  • Higher CD4(+) T cell counts associated with low viral pol replication capacity among treatment-naive adults in early HIV-1 infection JOURNAL OF INFECTIOUS DISEASES Barbour, J. D., Hecht, F. M., Wrin, T., Segal, M. R., Ramstead, C. A., Liegler, T. J., Busch, M. P., Petropoulos, C. J., Hellmann, N. S., Kahn, J. O., Grant, R. M. 2004; 190 (2): 251-256

    Abstract

    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.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.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 (

    View details for Web of Science ID 000222254800006

    View details for PubMedID 15216458

  • Use of postexposure prophylaxis against HIV infection following sexual exposure does not lead to increases in high-risk behavior AIDS Martin, J. N., Roland, M. E., Neilands, T. B., Krone, M. R., Bamberger, J. D., Kohn, R. P., Chesney, M. A., Franses, K., Kahn, J. O., Chesney, M. A., Franses, K., Kahn, J. O., Coates, T. J., Katz, M. H. 2004; 18 (5): 787-792

    Abstract

    The effectiveness of postexposure prophylaxis (PEP) following occupational exposure to HIV has prompted advocacy for PEP following sexual or drug-use exposures.To evaluate the concern that the availability of PEP for sexual or drug-use exposures might result in behavioral disinhibition.Non-randomized trial of 397 adults with high-risk sexual or drug-use exposures within the prior 72 h.Antiretroviral medication for 4 weeks and five counseling sessions.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.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.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.

    View details for DOI 10.1097/01.aids.0000111465.61782.2d

    View details for Web of Science ID 000221090800010

    View details for PubMedID 15075514

  • Cost-effectiveness of postexposure prophylaxis after sexual or injection-drug exposure to human immunodeficiency virus ARCHIVES OF INTERNAL MEDICINE Pinkerton, S. D., Martin, J. N., Roland, M. E., Katz, M. H., Coates, T. J., Kahn, J. O. 2004; 164 (1): 46-54

    Abstract

    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.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.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.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.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.

    View details for Web of Science ID 000188045200005

    View details for PubMedID 14718321

  • Primary HIV Infection. Current infectious disease reports Hare, C. B., Kahn, J. O. 2004; 6 (1): 65-71

    Abstract

    Primary HIV infection is a critical and highly dynamic time period in the course of HIV infection. The initial pathologic processes are important in determining long-term disease progression. In the absence of our ability to eradicate the virus, identifying individuals during primary HIV infection and performing interventions that optimize outcome are important to provide adequate care to a newly infected patient and, from a public health perspective, to identify sexual networks and provide a platform to reduce HIV exposures during a time of high viremia.

    View details for PubMedID 14733851

  • Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection AIDS Altfeld, M., Addo, M. A., Rosenberg, E. S., Hecht, F. A., Lee, P. K., Vogel, M., Yu, X. G., Draenert, R., Johnston, M. N., Strick, D., Allen, T. A., Feeney, M. E., Kahn, J. O., Sekaly, R. P., Levy, J. A., Rockstroh, J. K., Goulder, P. J., Walker, B. D. 2003; 17 (18): 2581-2591

    Abstract

    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.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.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.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.

    View details for DOI 10.1097/01.aids.0000096870.36052.b6

    View details for Web of Science ID 000220672800005

    View details for PubMedID 14685052

  • 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 AIDS RESEARCH AND HUMAN RETROVIRUSES Smith, D. E., Kaufmann, G. R., Kahn, J. O., Hecht, F. M., Grey, P. A., Zaunders, J. J., Cunningham, P. H., Carr, A., Duncombe, C., Quan, D. C., Petersen, A., Cooper, D. A. 2003; 19 (3): 189-199

    Abstract

    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.

    View details for Web of Science ID 000181551000004

    View details for PubMedID 12689411

  • Predicting the transmission of drug-resistant HIV: comparing theory with data LANCET INFECTIOUS DISEASES Blower, S. M., Aschenbach, A. N., Kahn, J. O. 2003; 3 (1): 10-11

    View details for Web of Science ID 000180201400016

    View details for PubMedID 12505024

  • Preventing hepatitis A and hepatitis B virus infections among men who have sex with men CLINICAL INFECTIOUS DISEASES Kahn, J. 2002; 35 (11): 1382-1387

    Abstract

    Hepatitis A and hepatitis B are 2 common sexually transmitted diseases that are preventable by vaccination. Men who have sex with men (MSM) are at increased risk of acquiring hepatitis A virus and hepatitis B virus through sexual exposure. Current guidelines from the Centers for Disease Control and Prevention recommend that MSM receive immunizations against hepatitis A and hepatitis B. Many health care providers and most MSM are unaware of the risks and the potentially dangerous consequences posed by hepatitis A and B virus infection, and the MSM thus remain unvaccinated and unprotected from exposure to these viruses. It is important for health care providers to educate and vaccinate their at-risk male patients against hepatitis A and hepatitis B virus infections.

    View details for Web of Science ID 000179336800012

    View details for PubMedID 12439802

  • Time trends in primary HIV-1 drug resistance among recently infected persons JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Grant, R. M., Hecht, F. M., Warmerdam, M., Liu, L., Liegler, T., Petropoulos, C. J., Hellmann, N. S., Chesney, M., Busch, M. P., Kahn, J. O. 2002; 288 (2): 181-188

    Abstract

    Transmission of multiclass drug-resistant human immunodeficiency virus type 1 (HIV-1) may increase with wider use of antiretroviral therapy.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.Consecutive case series of 225 patients referred to a San Francisco, Calif, hospital with recent HIV-1 infection from June 1996 through June 2001.Time trends in the prevalence of genotypic and phenotypic primary drug resistance.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).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.

    View details for Web of Science ID 000176711100018

    View details for PubMedID 12095382

  • 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 JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Gascon, R. L., Narvaez, A. B., Zhang, R. Z., Kahn, J. O., Hecht, F. M., Herndier, B. G., McGrath, M. S. 2002; 30 (2): 146-153

    Abstract

    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.

    View details for DOI 10.1097/01.QA1.0000017720.31903.6E

    View details for Web of Science ID 000176913400002

    View details for PubMedID 12045676

  • Use of laboratory tests and clinical symptoms for identification of primary HIV infection AIDS Hecht, F. M., Busch, M. P., Rawal, B., Webb, M., Rosenberg, E., Swanson, M., Chesney, M., Anderson, J., Levy, J., Kahn, J. O. 2002; 16 (8): 1119-1129

    Abstract

    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).Prospective cohort in a university research program.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.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.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.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.

    View details for Web of Science ID 000175760600005

    View details for PubMedID 12004270

  • Development of WF10, a novel macrophage-regulating agent. Current opinion in investigational drugs McGrath, M. S., Kahn, J. O., Herndier, B. G. 2002; 3 (3): 365-373

    Abstract

    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.

    View details for PubMedID 12054081

  • Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Barditch-Crovo, P., Deeks, S. G., Collier, A., Safrin, S., Coakley, D. F., Miller, M., Kearney, B. P., Coleman, R. L., Lamy, P. D., Kahn, J. O., McGowan, I., Lietman, P. S. 2001; 45 (10): 2733-2739

    Abstract

    Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.

    View details for Web of Science ID 000171154500010

    View details for PubMedID 11557462

  • Predicting the unpredictable: Transmission of drug-resistant HIV NATURE MEDICINE Blower, S. M., Aschenbach, A. N., Gershengorn, H. B., Kahn, J. O. 2001; 7 (9): 1016-1020

    Abstract

    We use a mathematical model to understand (from 1996 to 2001) and to predict (from 2001 to 2005) the evolution of the epidemic of drug-resistant HIV in San Francisco. We predict the evolutionary trajectories for 1,000 different drug-resistant strains with each strain having a different fitness relative to a drug-sensitive strain. We calculate that the current prevalence of resistance is high, and predict it will continue to rise. In contrast, we calculate that transmission of resistance is currently low, and predict it will remain low. We show that the epidemic of resistance is being generated mainly by the conversion of drug-sensitive cases to drug-resistant cases, and not by the transmission of resistant strains. We also show that transmission of resistant strains has not increased the overall number of new HIV infections. Our results indicate that transmission of resistant strains is, and will remain, a relatively minor public health problem.

    View details for Web of Science ID 000170853300026

    View details for PubMedID 11533704

  • Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection JOURNAL OF EXPERIMENTAL MEDICINE Altfeld, M., Rosenberg, E. S., Shankarappa, R., Mukherjee, J. S., Hecht, F. M., Eldridge, R. L., Addo, M. M., Poon, S. H., Phillips, M. N., Robbins, G. K., Sax, P. E., Boswell, S., Kahn, J. O., Brander, C., Goulder, P. J., Levy, J. A., Mullins, J. I., Walker, B. D. 2001; 193 (2): 169-180

    Abstract

    Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

    View details for Web of Science ID 000166431400005

    View details for PubMedID 11148221

  • Longitudinal analysis of T-cell receptor gene use by CD8(+) T cells in early human immunodeficiency virus infection in patients receiving highly active antiretroviral therapy BLOOD Schito, A. M., Vittinghoff, E., Hecht, F. M., Elkins, M. K., Kahn, J. O., Levy, J. A., Oksenberg, J. R. 2001; 97 (1): 214-220

    Abstract

    The effects of early antiretroviral therapy on the peripheral CD8(+) T-cell population were assessed by sequentially determining the T-cell receptor (TCR) repertoire complexity in a cohort of 15 individuals recently diagnosed with human immunodeficiency virus infection. Analysis was based on quantitative TCR variable B gene (TCRBV) usage and complementary-determining region 3 length assessment. Repertories were assessed at baseline and at weeks 2, 4, 12, 24, and 72 after initiation of therapy. Early administration of highly active antiretroviral therapy has a positive effect on the preservation and homeostasis of the CD8(+) cell repertoire. Nevertheless, differences from average baseline and control TCR profiles and initial development of repertoire perturbations were observed. The findings suggest that additional therapeutic protocols will be required during primary infection to significantly prevent long-term erosion of the T-cell-mediated immune response.

    View details for Web of Science ID 000166177300027

    View details for PubMedID 11133763

  • Reduction in CD8+ cell noncytotoxic anti-HIV activity in individuals receiving highly active antiretroviral therapy during primary infection. Proc Natl Acad Sci USA Stranford SA, Ong JC, Martinez-Marino B, Busch M, Hecht FM, Kahn J, Levy JA. 2001; 98 (2): 597-602
  • Evaluation of HIV-1 immunogen, an immunologic modifier, administered to patients infected with HIV having 300 to 549 x 10(6)/L CD4 cell counts - A randomized controlled trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Kahn, J. O., Cherng, D. W., Mayer, K., Murray, H., Lagakos, S. 2000; 284 (17): 2193-2202

    Abstract

    Despite enormous improvements achieved through the use of antiretroviral therapies (ARTs), the risk for eventual human immunodeficiency virus (HIV) disease progression remains high. Agents that enhance the immunologic mechanism for viral recognition might reduce disease progression.To determine whether the addition of HIV-1 Immunogen would confer added clinical efficacy to that achievable by ARTs.Multicenter, double-blind, placebo-controlled, randomized trial beginning March 1996 and ending May 1999 conducted at 77 centers in the United States providing primary care or referral care for persons infected with HIV.Adults infected with HIV who have baseline CD4 cell counts between 300 x 10(6)/L and 549 x 10(6)/L without prior acquired immunodeficiency syndrome-defining conditions receiving stable ART (or no therapy) were screened and 2527 were randomized.Ten units of HIV-1 Immunogen, derived from a Zairian HIV isolate, inactivated and formulated with incomplete Freund adjuvant, was administered intramuscularly every 12 weeks. The placebo was incomplete Freund adjuvant. Changes in ARTs were allowed.HIV progression-free survival; secondary end points included overall survival, changes in HIV RNA, CD4 cell counts, CD4 percentage, body weight, and immunogenicity.The overall event rate was 1.8 per 100 person-years of follow-up. Fifty-three subjects developed clinical progression in each treatment group (relative risk [RR], 0.97; 95% confidence interval [CI], 0.66-1.42; P =.89). There were 19 and 23 deaths in the placebo and HIV-1 Immunogen groups, respectively (RR, 0.81; 95% CI, 0.44-1. 48; P =.49). There were no statistically significant differences between the groups with respect to changes in HIV RNA (P =.59), CD4 percentage (P =.63), or body weight (P =.89). Subjects in the HIV-1 Immunogen group had an increase in average CD4 cell count of approximately 10 x 10(6)/L greater than the placebo group (P =.02).HIV-1 Immunogen with unrestricted ART failed to demonstrate an increase in HIV progression-free survival. JAMA. 2000;284:2193-2202.

    View details for Web of Science ID 000090052600027

    View details for PubMedID 11056590

  • Current questions in HIV/AIDS research in California - Clinical sciences WESTERN JOURNAL OF MEDICINE Moss, N. E., Lemp, G., Bluthenthal, R., Goldsmith, M. A., Haubrich, R., Kahn, J. O. 2000; 173 (2): 121-124
  • From the cell to the community: AIDS research in California WESTERN JOURNAL OF MEDICINE Moss, N. E., Lemp, G., Bluthenthal, R., Goldsmith, M. A., Haubrich, R., Kahn, J. O. 2000; 173 (2): 119-121

    View details for Web of Science ID 000088554300028

    View details for PubMedID 10924438

  • Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy - A randomized controlled trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Davey, R. T., Murphy, R. L., Graziano, F. M., Boswell, S. L., Pavia, A. T., Cancio, M., Nadler, J. P., Chaitt, D. G., Dewar, R. L., Sahner, D. K., Duliege, A. M., Capra, W. B., Leong, W. P., Giedlin, M. A., Lane, H. C., Kahn, J. O. 2000; 284 (2): 183-189

    Abstract

    While interleukin 2 (IL-2) is capable of inducing a marked expansion of the CD4 T-lymphocyte pool, limited data exist on whether IL-2 treatment can add significantly to the immunologic and virologic effects of potent antiretroviral therapy (ART).To determine the rate and magnitude of CD4 cell recovery and viral suppression when using a combination therapy of IL-2 and ART compared with ART alone.Randomized, controlled multicenter trial conducted from April 1996 through April 1998 at 8 clinical sites in the United States.Eighty-two adult outpatients who were infected with human immunodeficiency virus (HIV) and had baseline CD4 cell counts of 200 x 10(6)/L to 500 x 10(6)/L and baseline RNA levels of fewer than 10,000 copies/mL were randomized; 78 completed the study.Thirty-nine patients were randomly assigned to receive a combination therapy of subcutaneous IL-2 (administered in 5-day courses every 8 weeks at a starting dosage of 7.5 mIU twice per day) and ART; 43 were to receive ART therapy alone.Interleukin 2 safety and differential effects on CD4 cell counts, CD4 cell percentages, and plasma HIV RNA levels.The mean (SD) percentage increase in CD4 cell counts at 1 year for patients who received IL-2 was 112% (113%) compared with 18% (35%) in recipients of ART alone (P<.001). Both groups had mean (SD) increases in CD4 cell percentage: from 20.4% (6.3%) to 32.3% (12.4%) for the combination therapy group compared with 20.4% (5.1%) to 23.0% (7.2%) for recipients of ART alone (P<.001). Using a sensitive viral RNA assay, mean viral load changes were -0.28 and 0.09 log(10) copies for IL-2 recipients and control patients, respectively (P=.03). Twenty (67%) of 30 evaluable patients receiving IL-2 achieved final viral loads of fewer than 50 copies/mL compared with 13 (36%) of 36 control patients (P=.02). Toxic effects were common among patients who received IL-2 and were managed with antipyretics, hydration, rest, and dosage reduction as needed.Intermittent therapy with IL-2 and ART produced a substantially greater increase in CD4 cells and was associated with a larger decrease in viral load than ART alone. Clinical end-point trials will be necessary to determine whether the enhanced viral suppression and CD4 cell increases associated with IL-2 therapy will translate into improved clinical outcomes. JAMA. 2000;284:183-189

    View details for Web of Science ID 000087933100022

    View details for PubMedID 10889591

  • Quantitative and cost comparison of ultrasensitive human immunodeficiency virus type 1 RNA viral load assays: Bayer bDNA Quantiplex versions 3.0 and 2.0 and Roche PCR Amplicor Monitor version 1.5 JOURNAL OF CLINICAL MICROBIOLOGY Elbeik, T., Charlebois, E., Nassos, P., Kahn, J., Hecht, F. M., Yajko, D., Ng, V., Hadley, K. 2000; 38 (3): 1113-1120

    Abstract

    Quantification of human immunodeficiency virus type 1 (HIV-1) RNA as a measure of viral load has greatly improved the monitoring of therapies for infected individuals. With the significant reductions in viral load now observed in individuals treated with highly active anti-retroviral therapy (HAART), viral load assays have been adapted to achieve greater sensitivity. Two commercially available ultrasensitive assays, the Bayer Quantiplex HIV-1 bDNA version 3.0 (bDNA 3.0) assay and the Roche Amplicor HIV-1 Monitor Ultrasensitive version 1.5 (Amplicor 1.5) assay, are now being used to monitor HIV-1-infected individuals. Both of these ultrasensitive assays have a reported lower limit of 50 HIV-1 RNA copies/ml and were developed from corresponding older generation assays with lower limits of 400 to 500 copies/ml. However, the comparability of viral load data generated by these ultrasensitive assays and the relative costs of labor, disposables, and biohazardous wastes were not determined in most cases. In this study, we used matched clinical plasma samples to compare the quantification of the newer bDNA 3.0 assay with that of the older bDNA 2.0 assay and to compare the quantification and costs of the bDNA 3.0 assay and the Amplicor 1.5 assay. We found that quantification by the bDNA 3.0 assay was approximately twofold higher than that by the bDNA 2.0 assay and was highly correlated to that by the Amplicor 1.5 assay. Moreover, cost analysis based on labor, disposables, and biohazardous wastes showed significant savings with the bDNA 3.0 assay as compared to the costs of the Amplicor 1.5 assay.

    View details for Web of Science ID 000085742200028

    View details for PubMedID 10699005

  • Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214. J Infect Dis Schooley RT, Spino C, Kuritzkes D, Walker BD, Valentine FA, Hirsch MS, Cooney E, Friedland G, Kundu S, Merigan TC Jr, McElrath MJ, Collier A, Plaeger S, Mitsuyasu R, Kahn J, Haslett P, Uherova P, deGruttola V, Chiu S, Zhang B, Jones G, Bell D, Ketter N, Twadell T, Chernoff D, Rosandich M 2000; 182 (5): 1357-64
  • Efficacy and safety of adefovir dipivoxil with antiretroviral therapy - A randomized controlled trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Kahn, J., Lagakos, S., Wulfsohn, M., Cherng, D., Miller, M., Cherrington, J., Hardy, D., Beall, G., Cooper, R., Murphy, R., Basgoz, N., Ng, E., Deeks, S., Winslow, D., Toole, J. J., Coakley, D. 1999; 282 (24): 2305-2312

    Abstract

    Adefovir dipivoxil is a nucleotide analog that has demonstrated effective antiretroviral activity against human immunodeficiency virus (HIV) with once-daily administration.To determine if adefovir confers antiretroviral or immunologic benefit when added to stable antiretroviral therapy.Multicenter, 24-week, randomized, double-blind, placebo-controlled study. Enrollment was conducted from June 3, 1996, through May 6, 1997.Thirty-three US HIV treatment centers.Of 1171 patients screened, 442 patients infected with HIV receiving stable antiretroviral therapy for at least 8 weeks with plasma HIV RNA greater than 2500 copies/mL and CD4+ cell count above 0.20 x 10(9)/L were randomized.Patients were randomized to receive either a single 120-mg/d dose of adefovir dipivoxil (n = 219) or an indistinguishable placebo (n = 223). All patients received L-carnitine, 500 mg/d. Open-label adefovir was offered after 24 weeks and was continued until the end of the study.Changes in HIV RNA from baseline, based on area under the curve and CD4+ cell levels, adverse events, and effect of baseline genotypic resistance on response to adefovir.Patients assigned to adefovir demonstrated a 0.4-log10 decline from baseline in HIV RNA compared with no change in the placebo group (P<.001), which continued through 48 weeks. CD4+ cell counts did not change. During the initial 24 weeks, elevated hepatic enzyme levels (P<.001), gastrointestinal tract complaints (P<.001), and weight loss (P<.001) were associated with use of adefovir. Between 24 weeks and 48 weeks elevations in serum creatinine occurred in 60% of patients, usually returning to baseline after discontinuation of adefovir. Patients with lamivudine or lamivudine and zidovudine resistance mutations demonstrated anti-HIV effects with adefovir (P< or =.01 vs placebo group).This study suggests that once-daily adefovir therapy reduces HIV RNA and is active against isolates resistant to lamivudine or lamivudine and zidovudine. Nephrotoxicity occurred when treatment extended beyond 24 weeks but was reversible.

    View details for Web of Science ID 000084261700023

    View details for PubMedID 10612317

  • Antibody and cellular immune responses in breakthrough infection subjects after HIV type 1 glycoprotein 120 vaccination AIDS RESEARCH AND HUMAN RETROVIRUSES Locher, C. P., Grant, R. M., Collisson, E. A., Reyes-Teran, G., Elbeik, T., Kahn, J. O., Levy, J. A. 1999; 15 (18): 1685-1689

    Abstract

    HIV-specific antibodies and CD8+ T cell antiviral responses were evaluated in three human immunodeficiency virus 1 (HIV-1) gp120 vaccine recipients who later became infected with HIV-1. Titers of neutralizing antibody to the HIV-1(SF2) vaccine isolate were boosted, but titers of antibody to the autologous infecting viruses were never high and required at least 6 months after HIV infection to develop. Similarly, a marginal noncytotoxic CD8+ T cell antiviral response was observed only in one of the three vaccinees 3 months after HIV-1 infection. The infecting virus isolates had several amino acid substitutions in the HIV-1 envelope V3 region but were similar to other regional HIV-1 clade B isolates. Viral loads were similar to those of other HIV-1-infected individuals who had not been vaccinated and transient CD4+ T cell declines were observed in each person, suggesting that the vaccine was not effective at controlling these prognostic markers early in infection.

    View details for Web of Science ID 000084146700041

    View details for PubMedID 10606091

  • Building and testing an effective HIV vaccine WESTERN JOURNAL OF MEDICINE Kahn, J. 1999; 171 (5-6): 363-365

    View details for Web of Science ID 000084352100035

    View details for PubMedID 10639877

  • Booster immunization of HIV-1 negative volunteers with HGP-30 vaccine induces protection against HIV-1 virus challenge in SCID mice. Vaccine Sarin PS, Talmadge JE, Heseltine P, Murcar N, Gendelman HE, Coleman R, Kelsey L, Beckner S, Winship D, Kahn J. 1999; 17 (1): 64-71
  • A randomized, controlled, double-blind study comparing the survival benefit of four different reverse transcriptase inhibitor therapies (three-drug, two-drug, and alternating drug) for the treatment of advanced AIDS JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Henry, K., ERICE, A., Tierney, C., Balfour, H. H., Fischl, M. A., Kmack, A., Liou, S. H., Kenton, A., Hirsch, M. S., Phair, J., Martinez, A., Kahn, J. O. 1998; 19 (4): 339-349

    Abstract

    The primary objective was to compare the effects of dual or triple combinations of HIV-1 reverse transcriptase inhibitors with respect to survival. The time to new HIV disease progression or death, toxicities, the change in CD4 cells, and plasma HIV-1 RNA concentrations in a subset of study subjects were evaluated.This was a multicenter randomized, double-blind, placebo-controlled study.The study was conducted among 42 adult AIDS Clinical Trials Group sites and 7 National Hemophilia Foundation centers.1313 HIV-infected patients with CD4 counts < or = 50 cells/mm3 participated in this study, which was conducted from June 1993 to June 1996.Patients were randomized to one of four daily regimens containing 600 mg of zidovudine: zidovudine alternating monthly with 400 mg didanosine; zidovudine plus 2.25 mg of zalcitabine; zidovudine plus 400 mg of didanosine; or zidovudine plus 400 mg of didanosine plus 400 mg of nevirapine (triple therapy).The main outcome was survival (i.e., time to death).A significant difference in survival time was found between the four treatment groups, favoring those assigned to triple therapy (p = .02). A significant difference was also found in the delay of disease progression or death among the four treatment arms favoring the group assigned to triple therapy (p = .002). Baseline CD4 cell counts and plasma HIV-1 RNA concentrations as well as changes of CD4 counts at week 8 predicted survival for subjects in the virology substudy.In the pre-protease inhibitor era, a combination of triple reverse transcriptase inhibitors prolonged life and delayed disease progression in AIDS patients with advanced immune suppression.

    View details for Web of Science ID 000077070300004

    View details for PubMedID 9833742

  • Safety, pharmacokinetics, and antiretroviral activity of intravenous 9-[2-(R)-(phosphonomethoxy)propyl]adenine a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Deeks, S. G., Barditch-Crovo, P., Lietman, P. S., Hwang, F., Cundy, K. C., Rooney, J. F., Hellmann, N. S., Safrin, S., Kahn, J. O. 1998; 42 (9): 2380-2384

    Abstract

    9-[2-(R)-(Phosphonomethoxy)propyl]adenine (PMPA) is a nucleotide analogue with potent antiretroviral activity in vitro and in simian models. A randomized, double-blind, placebo-controlled, dose-escalation clinical trial of intravenous PMPA monotherapy was conducted in 20 human immunodeficiency virus (HIV)-infected adults with CD4 cell counts of >/=200 cells/mm3 and plasma HIV RNA levels of >/=10,000 copies/ml. Two dose levels were evaluated (1 and 3 mg/kg of body weight/day). Ten subjects were enrolled at each dose level (eight randomized to receive PMPA and two randomized to receive placebo). On day 1, a single dose of PMPA or placebo was administered by intravenous infusion. Beginning on study day 8, PMPA or placebo was administered once daily for an additional 7 consecutive days. All subjects tolerated dosing without significant adverse events. Mean peak serum PMPA concentrations were 2.7 +/- 0.9 and 9.1 +/- 2.1 microgram/ml in the 1- and 3-mg/kg cohorts, respectively. Serum concentrations declined in a biexponential fashion, with a terminal half-life of 4 to 8 h. At 3 mg/kg/day, a single infusion of PMPA resulted in a 0.4 log10 median decline in plasma HIV RNA by study day 8. Following 7 consecutive days of study drug administration thereafter, the median changes in plasma HIV RNA from baseline were -1.1, -0.6, and 0.1 log10 in the 3-mg/kg/day, 1-mg/kg/day, and placebo dose groups, respectively. Following the final dose in the 3-mg/kg/day cohort, the reduction in HIV RNA was sustained for 7 days before returning toward baseline. Further studies evaluating an oral prodrug of PMPA are under way.

    View details for Web of Science ID 000075737400041

    View details for PubMedID 9736567

  • Sexual transmission of an HIV-1 variant resistant to multiple reverse-transcriptase and protease inhibitors NEW ENGLAND JOURNAL OF MEDICINE Hecht, F. M., Grant, R. M., Petropoulos, C. J., Dillon, B., Chesney, M. A., Tian, H., Hellmann, N. S., Bandrapalli, N. I., Digilio, L., Branson, B., Kahn, J. O. 1998; 339 (5): 307-311

    View details for Web of Science ID 000075031400004

    View details for PubMedID 9682043

  • Acute human immunodeficiency virus type 1 infection NEW ENGLAND JOURNAL OF MEDICINE Kahn, J. O., Walker, B. D. 1998; 339 (1): 33-39

    View details for Web of Science ID 000074500000007

    View details for PubMedID 9647878

  • New testing strategy to detect early HIV-1 infection for use in incidence estimates and for clinical and prevention purposes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Janssen, R. S., Satten, G. A., Stramer, S. L., Rawal, B. D., O'Brien, T. R., Weiblen, B. J., Hecht, F. M., Jack, N., Cleghorn, F. R., Kahn, J. O., Chesney, M. A., Busch, M. P. 1998; 280 (1): 42-48

    Abstract

    Differentiating individuals with early human immunodeficiency virus 1 (HIV-1) infection from those infected for longer periods is difficult but important for estimating HIV incidence and for purposes of clinical care and prevention.To develop and validate a serologic testing algorithm in which HIV-1-positive persons with reactive test results on a sensitive HIV-1 enzyme immunoassay (EIA) but nonreactive results on a less sensitive (LS) EIA are identified as having early infection.Diagnostic test and testing strategy development, validation, and application. Specimens were tested with both a sensitive HIV-1 EIA (3A11 assay) and a less sensitive modification of the same EIA (3A11-LS assay).For assay development: 104 persons seroconverting to HIV-1 comprising 38 plasma donors, 18 patients of a sexually transmitted disease clinic in Trinidad, and 48 participants in the San Francisco Men's Health Study (SFMHS); 268 men without the acquired immunodeficiency syndrome (AIDS) in the SFMHS who had been infected for at least 2.5 years; and 207 persons with clinical AIDS; for testing strategy validation: 488 men in the SFMHS from 1985 through 1990 and 1275449 repeat blood donors at 3 American Red Cross blood centers from 1993 through 1995; and for HIV-1 incidence estimates: 2717910 first-time blood donors. We retrospectively identified persons eligible for a study of early infection.Ability to identify early HIV infection.Estimated mean time from being 3A11 reactive/3A11-LS nonreactive to being 3A11 reactive/3A11-LS reactive was 129 days (95% confidence interval [CI], 109-149 days) [corrected]. Our testing strategy accurately diagnosed 95% of persons with early infection; however, 0.4% (1/268) of men with established infection and 2% (5/207) of persons with late-stage AIDS were misdiagnosed as having early HIV-1 infection. Average yearly incidence estimates in SFMHS subjects were 1.5% per year vs observed average incidence of 1.4 per 100 person-years. Incidence in repeat blood donors using the sensitive/less sensitive assay testing strategy was 2.95 per 100000 per year (95% CI, 1.14-6.53/100000) vs observed incidence of 2.60 per 100000 person-years (95% CI, 1.49-4.21/100000). Overall incidence in first-time blood donors was 7.18 per 100000 per year (95% CI, 4.51-11.20/100000) and did not change statistically significantly between 1993 and 1996. Use of the sensitive/less sensitive testing strategy alone would have identified all 17 persons with antibodies to HIV-1 eligible for a study of early HIV-1 infection and would have increased enrollment.The sensitive/less sensitive testing strategy provides accurate diagnosis of early HIV-1 infection, provides accurate estimates of HIV-1 incidence, can facilitate clinical studies of early HIV-1 infection, and provides information on HIV-1 infection duration for care planning.

    View details for Web of Science ID 000074379400022

    View details for PubMedID 9660362

  • Evolutionary pattern of human immunodeficiency virus (HIV) replication and distribution in lymph nodes following primary infection: implications for antiviral therapy. Nat Med Pantaleo G, Cohen OJ, Schacker T, Vaccarezza M, Graziosi C, Rizzardi GP, Kahn J, Fox CH, Schnittman SM, Schwartz DH, Corey L, Fauci AS. 1998; 4 (3): 341-5
  • Post-exposure prevention of HIV-1 infection ANTIVIRAL THERAPY Kahn, J. O. 1998; 3: 45-47

    Abstract

    Post-exposure prevention of human immunodeficiency virus type 1 (HIV-1) infection involves a combined modality approach to subjects exposed to the HIV-1 virus through sexual or occupational contact or intravenous drug use. Identification of those at highest risk of transmission, which involves patient factors as well as the infectivity of the partner and the local prevalence of HIV-1, will help to determine appropriate candidates for post-exposure treatment. Early institution of therapy (within 72 h) should be followed with education and counselling to help maximize therapeutic adherence while reinforcing safer behaviour for the future.

    View details for Web of Science ID 000077354600009

    View details for PubMedID 10723509

  • Protease inhibitors do not increase the CD4+ cell count in HIV-uninfected individuals AIDS Res Hum Retroviruses Barker E, Kahn J, Fujimura S, Levy JA 1998; 12 (8): 1117-8
  • Success and Sadness JAMA Kahn JO 1998; 280 (1): 89
  • Risk behavior for HIV infection in participants in preventive HIV vaccine trials: A cautionary note JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Chesney, M. A., Chambers, D. B., Kahn, J. O. 1997; 16 (4): 266-271

    Abstract

    We conducted a longitudinal study of participants in phase I and II HIV vaccine safety and immunogenicity trials to examine changes in sexual risk behavior that are associated with risk of HIV transmission. The participants were 48 HIV-negative men and women enrolled in one of two placebo-controlled HIV vaccine trials conducted at San Francisco General Hospital. There was a significant increase in insertive unprotected anal intercourse (UAI) from 9% at baseline (trial entry), to 13% at the month 6 assessment, to 20% at the month 12 assessment (p = .02). The primary predictor of either insertive or receptive UAI during the vaccine trials was having engaged in this behavior prior to entry (p = .001). Higher-risk behavior was also seen among participants who were younger and had multiple sexual partners (each, p = .06) and who indicated that one of their reasons for participation in the vaccine trial was hope of protection from HIV infection (p = .07). These findings indicate that despite instructions otherwise, participants with a history of high-risk behavior or who express hope of protection from HIV infection by enrolling in vaccine trials may be candidates for more intensive risk-behavior counseling prior to and during their participation.

    View details for Web of Science ID A1997YK28700007

    View details for PubMedID 9402073

  • Predictors of survival in HIV-infected persons with 50 or fewer CD4 cells/mm(3) JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Spino, C., Kahn, J. O., Dolin, R., Phair, J. P. 1997; 15 (5): 346-355

    Abstract

    The objective of this study was to identify prognostic factors for survival in patients with pretreatment CD4 < or =50 cells/mm3 treated with nucleoside analogs, and to develop and validate a mortality risk model based on these factors. The design of the study consisted of retrospective analysis of AIDS Clinical Trials Group (ACTG) protocols 116a, 116b/117, 155, and 118. The setting was the multicenter AIDS Clinical Trials Group. The patients were HIV-infected with pretreatment CD4 < or =50 cells/mm3 and various degrees of prior zidovudine (ZDV) use. Double-blind, three-arm randomized control trials ACTG 116a and ACTG 116b/117 compared ZDV with didanosine (ddI). ACTG 155 compared ZDV with zalcitabine or combination therapy. Our validation study, ACTG 118, compared the effects of three different doses of ddI on survival. The main outcome measures were survival and mortality. The three studies combined enrolled 699 patients with entry CD4 T-lymphocyte counts of < or =50 cells/mm3. Forty percent of patients died during follow-up, with a median survival of 19.7 months. Multivariate analysis showed shorter survival at p < 0.0001 with lower CD4 count (relative hazard [RH] = 0.98) and lower hemoglobin level (RH = 0.81). Other factors included older age (RH = 1.03), male gender (RH = 1.70), Hispanic ethnicity (RH = 1.68), and symptomatic disease stage (RH = 2.06). Our predictive mortality risk model differentiated well patients with differing risks of mortality. When the risk model was applied to ACTG 118, the validation data set, the identified prognostic factors could distinguish patients with varying risks of death (p < 0.001, stratified log-rank test). These results demonstrate that CD4 T-lymphocytes counts < or =50 cells/mm3 should not be considered a precursor of imminent death; considerable variability in survival exists in severely immunocompromised patients. Our identification of prognostic indicators for survival can aid clinicians and patients in management of their disease and researchers in design of future clinical trials.

    View details for Web of Science ID A1997YC36400004

    View details for PubMedID 9342254

  • HIV-1 protease inhibitors - A review for clinicians JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Deeks, S. G., Smith, M., Holodniy, M., Kahn, J. O. 1997; 277 (2): 145-153

    Abstract

    The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (PIs). The 4 PIs available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented.A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996.Criteria used to select studies include their relevance to PIs, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care.Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4+ lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to PIs occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs.The PIs have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.

    View details for Web of Science ID A1997WA65000036

    View details for PubMedID 8990341

  • Neutralization of a clade B primary isolate by sera from human immunodeficiency virus-uninfected recipients of candidate AIDS vaccines J Infect Dis Zolla-Pazner S, Alving C, Belshe R, Berman P, Burda S, Chigurupati P, Clements ML, Duliege AM, Excler JL, Hioe C, Kahn J, McElrath MJ, Sharpe S, Sinangil F, Steimer K, Walker MC, Wassef N, Xu S 1997; 175 (4): 764-74
  • Predictors of survival in HIV-infected persons with 50 or fewer CD4 cells/mm3 J Acquir Immune Defic Syndr Spino C, Kahn JO; Dolin R; Phair JP 1997; 15: 346-55
  • Association of plasma human immunodeficiency virus type 1 RNA level with risk of clinical progression in patients with advanced infection JOURNAL OF INFECTIOUS DISEASES COOMBS, R. W., Welles, S. L., Hooper, C., REICHELDERFER, P. S., DAQUILA, R. T., JAPOUR, A. J., JOHNSON, V. A., Kuritzkes, D. R., Richman, D. D., Kwok, S., Todd, J., Jackson, J. B., DeGruttola, V., CRUMPACKER, C. S., Kahn, J. 1996; 174 (4): 704-712

    Abstract

    Human immunodeficiency virus (HIV)-1 RNA level in plasma was evaluated as a surrogate marker for disease progression in a clinical trial of advanced HIV-1 infection. Baseline HIV-1 RNA level was an independent predictor of disease progression (relative hazard [RH] for each doubling of HIV-1 RNA level, 1.26; 95% confidence interval [CI], 1.03-1.54; P = .02), after adjusting for the week 4 change in HIV-1 RNA level, baseline CD4 cell count, syncytium-inducing phenotype, clinical status at study entry, and therapy randomization. A 50% reduction in HIV-1 RNA level was associated with a 27% decrease in the adjusted risk of disease progression during the study (RH, 0.73; 95% CI, 0.52-1.02; P = .07). The partial validation of HIV-1 RNA as a predictor for clinical end points has implications for the use of HIV-1 RNA in clinical trials and practice.

    View details for Web of Science ID A1996VK04500004

    View details for PubMedID 8843206

  • Prognostic value of plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in patients with advanced HIV-1 disease and with little or no prior zidovudine therapy. AIDS Clinical Trials Group Protocol 116A/116B/117 Team. journal of infectious diseases Welles, S. L., Jackson, J. B., Yen-Lieberman, B., Demeter, L., JAPOUR, A. J., Smeaton, L. M., JOHNSON, V. A., Kuritzkes, D. R., D'Aquila, R. T., Reichelderfer, P. A., Richman, D. D., REICHMAN, R., Fischl, M., Dolin, R., COOMBS, R. W., Kahn, J. O., McLaren, C., Todd, J., Kwok, S., CRUMPACKER, C. S. 1996; 174 (4): 696-703

    Abstract

    The association of plasma human immunodeficiency virus type 1 (HIV-1) RNA level at study entry and over time with clinical progression was evaluated in 187 patients from AIDS Clinical Trials Group protocol 116A who had little or no prior zidovudine treatment. Three-fold-higher HIV-1 RNA levels at study entry and 3-fold increases by week 8 were associated with progression (relative hazard [RH], 1.67; 95% confidence limits [CL], 1.20, 2.32; and RH, 1.45; CL, 1.02, 2.05, respectively). Having 3-fold-higher CD4 cell count at entry was independently associated with a 52% reduction in risk for progression (adjusted RH, 0.48; CL, 0.33, 0.70). When stratified by length of prior zidovudine therapy, RNA level was predictive in drug-naive patients (adjusted RH, 1.87; CL, 1.23, 2.85) but not predictive in patients with up to 16 weeks of prior therapy (adjusted RH, 1.11; CL, 0.70, 1.76). Analysis suggests that the acquisition of mutations at HIV-1 reverse transcriptase codons 215 and 74 is associated with subsequent increases in HIV-1 RNA level (relative risk, 7.00; CL, 0.86, 56.90).

    View details for PubMedID 8843205

  • Patterns of opportunistic infections in patients with HIV infection J Acquir Immune Defic Syndr Finkelstein DM, Williams PL, Molenberghs G, Feinberg J, Powderly WG, Kahn J, Dolin R, Cotton D 1996; 12: 38-45
  • Pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor: the effects of zidovudine J Clinical Pharm Aweeka FT, Kwong M; Mak M; al-Uzri A; Affrime M; Cutler D; Kahn J; Gambertoglio JG 1996; 36 (1): 107-113
  • Phase 1 study of combination therapy with L-697, 661 and zidovudine j Acquir Immune Defic Syndr Schooley RT, Campbell TB; Kuritzkes DR; Blaschke T; Stein DS; Rosandich ME; Phair J; Pottage JC; Messari F; Collier A; Kahn, J for the ACTG 184 Protocol Team 1996; 12: 363-70
  • WEEKLY ORAL ETOPOSIDE IN PATIENTS WITH KAPOSIS-SARCOMA ASSOCIATED WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION - A PHASE-I MULTICENTER TRIAL OF THE AIDS CLINICAL-TRIALS GROUP JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Paredes, J., Kahn, J. O., Tong, W. P., Feldstein, M. L., Lin, S. L., Bennett, J. M., METROKA, C. E., Ratner, L., Krown, S. E. 1995; 9 (2): 138-144

    Abstract

    We conducted a Phase I trial to evaluate the safety, maximally tolerated dose (MTD), antitumor activity, and pharmacology of once-weekly oral etoposide in patients with Kaposi's sarcoma (KS) and AIDS. From September 1990 to October 1991, 27 eligible patients with biopsy-confirmed KS were treated at six etoposide dose levels, ranging from 150 to 400 mg weekly. Patients were treated until their tumor progressed or until unacceptable toxicity developed. On the first day of therapy, etoposide plasma concentrations were measured by high-performance liquid chromatography. The MTD was defined as the etoposide dose that induced reversible grade 3 toxicity in three of six patients during the first 4 weeks. Although dose-limiting toxicity was uncommon during the first 4 weeks of treatment (three of 27 patients), and the MTD was not reached, with longer treatment > 50% of patients developed dose-limiting toxicities, most commonly neutropenia. Responses were observed at all dosage levels (except 350 mg weekly), with partial tumor regression documented in nine (36%) of 25 evaluable patients. There was marked variability in etoposide area under the plasma concentration versus time curve, elimination half-time (t1/2), and urinary excretion. These pharmacokinetic features were not, however, associated with the presence of gastrointestinal symptoms, the severity of side effects, or tumor response. We conclude that weekly oral etoposide can be safely administered to patients with AIDS and KS. The observed antitumor effects over a wide range of doses support further studies with very low and minimally toxic etoposide doses, alone or in combination with other agents.

    View details for Web of Science ID A1995QY96300006

    View details for PubMedID 7749790

  • CLINICAL, IMMUNOLOGICAL, AND VIROLOGICAL OBSERVATIONS RELATED TO HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) TYPE-I INFECTION IN A VOLUNTEER IN AN HIV-1 VACCINE CLINICAL-TRIAL JOURNAL OF INFECTIOUS DISEASES Kahn, J. O., Steimer, K. S., Baenziger, J., Duliege, A. M., Feinberg, M., Elbeik, T., Chesney, M., Murcar, N., Chernoff, D., Sinangil, F. 1995; 171 (5): 1343-1347

    Abstract

    A vaccine breakthrough occurred in a phase 1 clinical trial of a human immunodeficiency virus (HIV) type 1 candidate subunit vaccine. The vaccine antigen, gp120SF2, is a fully glycosylated protein produced in mammalian cells from the HIVSF2 isolate. After 4 immunizations, the subject developed neutralizing antibodies and lymphoproliferative responses to the gp120 protein. About 18 weeks after the last immunization, the subject became HIV infected. During the acute phase of infection, there was high virus burden, a decline in CD4+ T lymphocytes, increases in rgp120SF2-binding antibodies and HIVSF2- and HIVMN-neutralizing antibodies, and transient lymphoproliferative responses to HIV-1 envelope and core proteins. The nucleotide sequence of the V3 loop from 2 virus isolations displayed close similarity to the V3 sequence of the vaccine antigen. Thus, the immunologic responses induced by the vaccine in this subject did not protect him from HIV-1 infection.

    View details for Web of Science ID A1995QU64000040

    View details for PubMedID 7751714

  • PREVALENCE AND CLINICAL-SIGNIFICANCE OF ZIDOVUDINE RESISTANCE MUTATIONS IN HUMAN-IMMUNODEFICIENCY-VIRUS ISOLATED FROM PATIENTS AFTER LONG-TERM ZIDOVUDINE TREATMENT JOURNAL OF INFECTIOUS DISEASES JAPOUR, A. J., Welles, S., DAQUILA, R. T., JOHNSON, V. A., Richman, D. D., COOMBS, R. W., REICHELDERFER, P. S., Kahn, J. O., CRUMPACKER, C. S., Kuritzkes, D. R. 1995; 171 (5): 1172-1179

    Abstract

    Zidovudine resistance mutations at reverse transcriptase codons 215 or 41 were found in two-thirds of human immunodeficiency virus type 1 (HIV-1) isolates obtained at baseline from patients enrolled in an AIDS Clinical Trials Group (ACTG) protocol that compared didanosine with continued zidovudine in patients with > or = 16 weeks of previous zidovudine therapy (ACTG 116B/117). The combined presence of mutations at both codons 215 and 41 conferred an increased risk for progression (relative hazard, 1.82; 95% confidence interval [CI], 1.02-3.26) and an increased risk for death (RH, 5.42; 95% CI, 1.92-15.30) in analyses that controlled for other factors predictive of progression. However, the benefit of switching to didanosine compared with continued zidovudine therapy was independent of the presence of these mutations. Although this information is not helpful in determining when to alter therapy, detection of zidovudine resistance mutations provides prognostic information in patients with advanced HIV disease.

    View details for Web of Science ID A1995QU64000014

    View details for PubMedID 7538548

  • ZIDOVUDINE RESISTANCE AND HIV-1 DISEASE PROGRESSION DURING ANTIRETROVIRAL THERAPY ANNALS OF INTERNAL MEDICINE DAQUILA, R. T., JOHNSON, V. A., Welles, S. L., JAPOUR, A. J., Kuritzkes, D. R., DeGruttola, V., REICHELDERFER, P. S., COOMBS, R. W., CRUMPACKER, C. S., Kahn, J. O., Richman, D. D. 1995; 122 (6): 401-408

    Abstract

    To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine and clinical progression.Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comparison of didanosine with continued zidovudine therapy in patients with advanced HIV-1 disease who had received 16 weeks or more of previous zidovudine therapy.Participating ACTG virology laboratories.187 patients with baseline HIV-1 isolates.Zidovudine susceptibility testing and assays for syncytium-inducing phenotype were done on baseline HIV-1 isolates. Relative hazards for clinical progression or death associated with baseline clinical, virologic, and immunologic factors were determined from Cox proportional hazards regression models.Compared with other patients, 15% (26 of 170) with isolates showing high-level zidovudine resistance (50% inhibitory zidovudine concentration > or = 1.0 microM) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.21 to 6.39) in analyses that controlled for baseline CD4+ T-lymphocyte count, syncytium-inducing HIV-1 phenotype, disease stage, and randomized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly zidovudine-resistant baseline HIV-1 isolates.High-level resistance of HIV-1 to zidovudine predicted more rapid clinical progression and death when adjusted for other factors. However, patients with advanced HIV-1 disease may benefit from a change in monotherapy from zidovudine to didanosine whether high-level HIV-1 resistance to zidovudine is present or absent, and laboratory assessment of zidovudine resistance is not necessary for deciding when to switch monotherapy from zidovudine to didanosine.

    View details for Web of Science ID A1995QM26600001

    View details for PubMedID 7856987

  • HIV CARE - A CHANGING HEALTH-CARE SYSTEM JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Kahn, J. O., Smith, M. D. 1995; 8: S1-S3

    View details for Web of Science ID A1995QE65800001

    View details for PubMedID 7834409

  • HIV-1 p17 synthetic peptide vaccine HGP-30: induction of immune response in human subjects and preliminary evidence of protection against HIV challenge in SCID mice. Cell Mol Biol Sarin PS, Mora CA, Naylor PH, Markham R, Schwartz D, Kahn J, Heseltine P, Gazzard B, Youle M, Rios A, et al. 1995; 41 (3): 401-7
  • CLINICAL AND IMMUNOLOGICAL RESPONSES TO HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) TYPE 1(SF2) GP120 SUBUNIT VACCINE COMBINED WITH MF59 ADJUVANT WITH OR WITHOUT MURAMYL TRIPEPTIDE DIPALMITOYL PHOSPHATIDYLETHANOLAMINE IN NON-HIV-INFECTED HUMAN VOLUNTEERS JOURNAL OF INFECTIOUS DISEASES Kahn, J. O., Sinangil, F., Baenziger, J., Murcar, N., Wynne, D., Coleman, R. L., Steimer, K. S., Dekker, C. L., Chernoff, D. 1994; 170 (5): 1288-1291

    Abstract

    A phase 1 study of 42 non-human immunodeficiency virus type 1 (HIV)-infected volunteers was initiated to determine the safety and immunogenicity of an HIV subunit vaccine consisting of recombinant envelope gp120 derived from HIVSF2 (rgp120SF2) combined with a novel adjuvant, MF59, with or without the immunomodulator muramyl tripeptide dipalmitoyl phosphatidylethanolamine (MTP-PE). All injections contained adjuvant MF59, and subjects were grouped according to MTP-PE dose. Injections were given on days 0, 30, 180, and 365. The vaccine was well tolerated with limited local and systemic reactions. These immunizations induced rgp120SF2-specific binding antibodies that persisted > or = 24 weeks. After three immunizations, all subjects receiving the antigen developed neutralizing antibodies to HIVSF2, and serum from 67% of these subjects also cross-neutralized HIVMN. ELISA-reactive antibodies to the HIVSF2 V3 region and strong lymphoproliferative responses to HIVSF2 envelope proteins were detected in all rgp120SF2-immunized subjects.

    View details for Web of Science ID A1994PN66800037

    View details for PubMedID 7963729

  • SAFETY, ACTIVITY, AND PHARMACOKINETICS OF GLQ223 IN PATIENTS WITH AIDS AND AIDS-RELATED COMPLEX ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Kahn, J. O., Gorelick, K. J., Gatti, G., ARRI, C. J., Lifson, J. D., Gambertoglio, J. G., Bostrom, A., WILLIAMS, R. 1994; 38 (2): 260-267

    Abstract

    GLQ223 is a highly purified single-chain ribosome-inactivating protein with selective effects against a variety of cells, including macrophages infected with human immunodeficiency virus. We evaluated the safety, pharmacokinetics, and immunologic effects of multiple doses of GLQ223 in 22 patients with AIDS or AIDS-related complex; CD4+ T-cell counts were between 100 and 350/mm3. GLQ223 was administered intravenously at doses of 8, 16, 24, 36, and 50 micrograms/kg of body weight; the drug was administered by constant infusion over 3 h to achieve a concentration in serum of 50 ng/ml; this concentration is known to be associated with anti-HIV effects in vitro. All patients reported a flu-like syndrome characterized by muscle and joint aches and an increase in creatinine kinase levels; symptoms were controlled easily. For patients who received 36 and 50 micrograms/kg, target concentrations in serum were achieved and an increase in CD4+ and CD8+ T cells was sustained; this sustained increase persisted for at least 28 days after the last infusion. beta 2-Microglobulin levels increased during the infusions and then declined when the infusions ended. Repeat infusions of GLQ223 were safe and relatively well tolerated. The target concentration of GLQ223 in serum was achieved and sustained. Our results suggest that GLQ223 may have activity in treating patients with human immunodeficiency virus infection.

    View details for Web of Science ID A1994MU93200020

    View details for PubMedID 7910722

  • URIC-ACID AND DIDANOSINE COMPLIANCE IN AIDS CLINICAL-TRIALS - AN ANALYSIS OF AIDS CLINICAL-TRIALS GROUP PROTOCOL-116A AND PROTOCOL-116B/117 JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Richardson, D., Liou, S. H., Kahn, J. O. 1993; 6 (11): 1212-1223

    Abstract

    An analysis is presented that promotes the use of uric acid levels as an indicator of patients didanosine (ddI) use. Logistic regression techniques were used on data from two test groups that best represent patients entered on ACTG protocols 116A and 116B/117. Two classification functions resulted that are based on serial uric acid measurements and were used to classify patients to one of two groups: those treated with zidovudine (ZDV) and those treated with ddI. These functions correctly classified well over 70% of the patients in each of these two studies. Implications of these results with respect to the assessment of ddI compliance and limitations in the use of these classification functions are discussed.

    View details for Web of Science ID A1993MC83000005

    View details for PubMedID 8229656

  • NEUROLOGICAL REACTIONS IN HIV-INFECTED PATIENTS TREATED WITH TRICHOSANTHIN NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY Garcia, P. A., Bredesen, D. E., Vinters, H. V., VONEINSIEDEL, R. G., Williams, R. L., Kahn, J. O., Byers, V. S., Levin, A. S., WAITES, L. A., Messing, R. O. 1993; 19 (5): 402-405

    Abstract

    Trichosanthin is a ribosome-inactivating protein that is being studied as a possible treatment for patients infected with human immunodeficiency virus (HIV). We report the clinical and pathological features in two patients who experienced neurological reactions to trichosanthin. Both patients were neurologically asymptomatic prior to treatment but developed coma and multifocal neurological deficits after treatment. Neuropathological examination revealed regions of severe, multifocal necrosis with histiocytic infiltrates. These reactions to trichosanthin may be mediated by soluble factors released by HIV-infected macrophages.

    View details for Web of Science ID A1993MB06300005

    View details for PubMedID 8278023

  • Vaccines directed against HIV: preventive and therapeutic strategies. AIDS clinical review Kahn, J. O., Birx, D. L. 1993: 213-238

    Abstract

    Vaccine therapy studies in HIV-seropositive volunteers over the next year should provide additional insights into whether different vaccine viral strains (LAI, IIIB, MN, SF2), different protein sources (whole virus particles, recombinant protein, peptides), different expression systems (baculovirus, mammalian), or different adjuvants (incomplete Freund's, MTP-PE, MF59, alum) generate significantly different immune responses at the cellular and humoral level. In addition, differences in the ability of each vaccine to induce humoral immune responses to epitopes in the constant regions vs. variable regions, contiguous or noncontiguous "conformational" epitopes, with high vs. low antibody affinity can be evaluated. The roles of antibody-dependent cellular cytotoxicity (ADCC), cellular recognition, nonspecific natural killing, and MHC-restricted cytotoxicity can also be explored. To date, the majority of the immunogens have proven to be safe. Many induce new humoral and cellular immune responses against HIV. The final important question remains, whether any of these vaccines used as therapeutic immunogens generate immune responses that induce an altered disease course with a prolonged asymptomatic period without immunodeficiency, whether vaccines can affect increased viral clearance, or decreased transmission/infectivity? There remains no in vitro assay known to correlate with lack of disease progression, no immune profile consistent with a prolonged asymptomatic period. The vaccine therapy trial researchers seek the answers to these important questions. No single research organization can begin to address all the possibilities, so the overall pace of exploration of this therapeutic concept is likely to be dictated by the level of cooperation between the many groups involved in these studies. Open collaboration between researchers and open exchange of reagents, immunogens for in vitro experiments, and sera will allow faster dissection of the many questions and issues raised in this chapter. Whether vaccine therapy proves to have a useful role in the treatment of HIV-1-induced disease, these studies will ultimately lead to the development of useful techniques and provide new insights into the nature of the immunological responses, as the investigation of vaccine therapy did over a century ago.

    View details for PubMedID 8217900

  • A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group. New England journal of medicine Kahn, J. O., Lagakos, S. W., Richman, D. D., Cross, A., Pettinelli, C., Liou, S. H., Brown, M., Volberding, P. A., CRUMPACKER, C. S., Beall, G. 1992; 327 (9): 581-587

    Abstract

    Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine.This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with less than or equal to 300 CD4 cells per cubic milliliter, or asymptomatic HIV infection with less than or equal to 200 CD4 cells per cubic milliliter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine.There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P less than 0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group.Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease.

    View details for PubMedID 1353607

  • A phase I study of HGP-30, a 30 amino acid subunit of the human immunodeficiency virus (HIV) p17 synthetic peptide analogue sub-unit vaccine in seronegative subjects. AIDS research and human retroviruses Kahn, J. O., Stites, D. P., Scillian, J., Murcar, N., Stryker, R., Volberding, P. A., Naylor, P. H., Goldstein, A. L., Sarin, P. S., Simmon, V. F. 1992; 8 (8): 1321-1325

    Abstract

    HGP-30-KLH vaccine in alum at doses of 10, 25, 50, and 100 micrograms/kg administered intramuscularly at weeks 0, 4, and 10 appear well-tolerated clinically. Local pain at the injection site, appears to be the main clinical toxicity. Laboratory parameters are not affected by administration of the vaccine candidate except for perhaps mild urinalysis abnormalities at the highest dose. This vaccine candidate has no apparent immunotoxicity and does not appear to affect lymphocyte populations or T-cell functional studies. Low levels and transient antibodies develop in a minority of subjects early after immunization with the vaccine candidate. These responses were observed in the lowest dose range. Higher doses, and longer follow-up will be needed to confirm this observation. T-cell proliferative responses to KLH and KLH-HGP-30 are consistent and may not be dose dependent, but the proliferative responses are variable and more data need to be accumulated. Preliminary, there appears to be an HGP-30-induced CTL response of HGP-30-coated EBV-transformed autologous B cell lines. This study was approved under an IND for the California Department of Health Services' Food and Drug Branch. They have provided excellent support and regulatory guidelines for this project. Future work will extend and confirm these initial observations.

    View details for PubMedID 1466950

  • AIDS-associated Kaposi's sarcoma. AIDS clinical review Kahn, J. O., Northfelt, D. W., Miles, S. A. 1992: 261-280

    Abstract

    The underlying degree of immune suppression is an important consideration in the selection of treatment for AIDS-KS. In general, subjects with CD4+ T lymphocytes greater than 500/mm3 require only local therapy unless there is some specific disability caused by the AIDS-KS lesions. Subjects with CD4+ T lymphocytes between 200 and 500/mm3 may respond to recombinant interferon. This therapy is effective in controlling AIDS-KS, can be combined with zidovudine, and has anti-HIV properties. If interferon-alpha with zidovudine is clinically ineffective, systemic chemotherapy may then be required. Subjects with AIDS-KS and CD4+ T lymphocytes less than 200/mm3 should receive PCP prophylaxis, may require systemic chemotherapy, and should be maintained on antiretroviral therapy. Therapy of AIDS-KS is not curative, and a treatment plan of the underlying immune deficiency is essential for planning and implementing rational therapy. AIDS-KS is rarely life threatening but often cosmetically and functionally disabling. Treatment plans remain focused on palliative goals and include reduction of extremity or facial edema, elimination of painful lesions, relief of gastrointestinal disturbances induced by AIDS-KS lesions (including symptoms of outlet obstruction, diarrhea, and rarely blood loss), and reduction of the pulmonary burden of AIDS-KS to improve oxygenation and relieve obstructive pneumonias.

    View details for PubMedID 1606060

  • PHASE-1 STUDY OF RECOMBINANT HUMAN CD4-IMMUNOGLOBULIN-G THERAPY OF PATIENTS WITH AIDS AND AIDS-RELATED COMPLEX ANTIMICROBIAL AGENTS AND CHEMOTHERAPY HODGES, T. L., Kahn, J. O., Kaplan, L. D., Groopman, J. E., Volberding, P. A., AMMAN, A. J., ARRI, C. J., BOUVIER, L. M., Mordenti, J., Izu, A. E., Allan, J. D. 1991; 35 (12): 2580-2586

    Abstract

    The safety and pharmacokinetics of recombinant CD4-immunoglobulin G (rCD4-IgG) were evaluated in a phase 1 study with dose escalation. A total of 16 patients, 6 with AIDS and 10 with AIDS-related complex, were evaluated at two university-affiliated hospital clinics. rCD4-IgG was administered once weekly for 12 weeks to four patients each at doses of 0.03, 0.1, 0.3, and 1.0 mg/kg of body weight. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Pharmacokinetic, toxicity, and immunologic variables were monitored with all patients. Administration of rCD4-IgG was well tolerated, with no important clinical or immunologic toxicities noted. No subjects required dose reduction or discontinuation of therapy due to toxicity. No consistent changes were seen in human immunodeficiency virus antigen levels in serum or CD4 lymphocyte populations. The volume of distribution was small, and compared with that of rCD4, the half-life of the hybrid molecule was markedly prolonged following intramuscular or intravenous administration. The rate and extent of absorption following intramuscular dosing were variable. Intramuscular administration of rCD4-IgG appears to be inferior to intravenous dosing from a pharmacokinetic standpoint, with lower peak concentrations and variable absorption. After intravenous administration, peak concentrations of rCD4-IgG in serum (20 to 24 micrograms/ml) that have shown antiviral activity in vitro against more sensitive clinical isolates of human immunodeficiency virus were achieved. The peak concentrations in serum after intramuscular administration were below these levels. Treatment with rCD4-IgG was well tolerated at the doses administered to patients in this study but did not result in significant changes in CD4 lymphocyte counts or p24 antigen levels in serum.

    View details for Web of Science ID A1991GT89000023

    View details for PubMedID 1810192

  • PHARMACOKINETICS OF GLQ223 IN RATS, MONKEYS, AND PATIENTS WITH AIDS OR AIDS-RELATED COMPLEX ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Gatti, G., Kahn, J. O., Lifson, J., WILLIAMS, R., Turin, L., Volberding, P. A., Gambertoglio, J. G. 1991; 35 (12): 2531-2537

    Abstract

    The pharmacokinetics of GLQ223 administered as a single short intravenous infusion to rats, monkeys, and patients with AIDS or AIDS-related complex (ARC) are presented. GLQ223 was given at a dose of 3,500 micrograms/kg of body weight to five Sprague-Dawley rats; a dose of 300 micrograms/kg was given to three cynomolgus monkeys; and doses of 1, 8, 16, 24, and 36 micrograms/kg were given to 10 patients with AIDS and 8 patients with ARC in an escalating dose design. Plasma clearance was 0.85 +/- 0.24 liter/h/kg in rats, 0.16 +/- 0.08 liter/h/kg in monkeys, and 0.13 +/- 0.07 liter/h/kg in patients with AIDS or ARC. The volume of distribution at steady state was 0.42 +/- 0.12, 0.21 +/- 0.20, and 0.18 +/- 0.50 liter/kg in rats, monkeys, and patients, respectively. The elimination half-life was 1.3 +/- 0.4, 3.7 +/- 1.5, and 3.2 +/- 1.0 h in rats, monkeys, and patients, respectively. The disposition of GLQ223 was not dose dependent within the dose range tested in patients with AIDS or ARC. Interspecies pharmacokinetic scaling resulted in a good linear correlation for plasma clearance and the volume of distribution at steady state plotted versus species body weight on a log-log scale, indicating the predictability of elimination and distribution of GLQ223 among species. Allometric equations derived may be useful for the prediction of doses and dosage regimens to be used in animal models.

    View details for Web of Science ID A1991GT89000015

    View details for PubMedID 1810186

  • Chemotherapy for AIDS-associated Kaposi's sarcoma. Oncology (Williston Park, N.Y.) Kahn, J., Northfelt, D., Volberding, P. 1991; 5 (10): 57-63

    Abstract

    Clinical staging and response criteria for AIDS-associated Kaposi's sarcoma (AIDS-KS) are not well-developed, but classifying patients into limited or extensive disease categories allows a clinician to select appropriate local or systemic therapy. A prospective staging system has been proposed to uniformly evaluate pretreatment patient characteristics and subsequent clinical responses. Combination chemotherapy is effective, but its use is often limited by toxicities. Antiretroviral medications, if clinically tolerated, should be continued during combination chemotherapy. Future therapies will evaluate the utility of ddI or ddC with combination chemotherapy. A second area of research involves combination therapy using chemotherapy and antiretroviral agents along with growth factors to limit myelotoxicity.

    View details for PubMedID 1838275

  • CLINICAL AND VIROLOGICAL EFFECTS OF RECOMBINANT HUMAN GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IN PATIENTS RECEIVING CHEMOTHERAPY FOR HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED NON-HODGKINS-LYMPHOMA - RESULTS OF A RANDOMIZED TRIAL JOURNAL OF CLINICAL ONCOLOGY Kaplan, L. D., Kahn, J. O., Crowe, S., Northfelt, D., Neville, P., Grossberg, H., Abrams, D. I., Tracey, J., Mills, J., Volberding, P. A. 1991; 9 (6): 929-940

    Abstract

    Thirty patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL) receiving chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomized to receive either subcutaneous recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) or no additional therapy. Recombinant rGM-CSF (at a dose of 10-20 micrograms/kg/d) was given on days 1 to 10 (early rGM-CSF) to the first five patients, but was changed to days 4 to 13 (delayed rGM-CSF) of each chemotherapy cycle in subsequent patients. Compared with the control group (N = 10), the delayed rGM-CSF group (N = 11) had higher mean nadirs of the absolute neutrophil count (0.36 v 0.89 x 10(9)/L; P = .009), shorter mean durations of neutropenia (4.9 v 1.3 days; P = .02), fewer chemotherapy cycles complicated by neutropenia and fever (67% v 27%; P = .001), fewer days hospitalized for fever and neutropenia (4.9 v 1.8; P = .004), fewer reductions in chemotherapy dosages, and less frequent delays in chemotherapy administration. No significant differences were observed between patients in the control group and those in the early rGM-CSF group (N = 5). Median levels of serum HIV-1 p24 antigen decreased to 18% and 17% of baseline values in control (N = 4) and rGM-CSF groups (N = 6), respectively, 1 week following administration of the first cycle of chemotherapy. In the third week after chemotherapy, median antigen levels remained below baseline in the control group, but rose to 243% of baseline values in the rGM-CSF group (P = .01), suggesting stimulation of HIV replication. The effect of this change in HIV activity on clinical outcome of treated patients could not be determined, and therefore the clinical significance of this finding remains unclear. Complete response rates of 67%, 70%, and 60% were observed in the control, delayed rGM-CSF, and early rGM-CSF groups, respectively, with corresponding survival times of 9.0, 11.4, and 8.0 months.

    View details for Web of Science ID A1991FP23800006

    View details for PubMedID 2033429

  • TREATMENT OF AIDS-RELATED KAPOSIS-SARCOMA HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Northfelt, D. W., Kahn, J. O., Volberding, P. A. 1991; 5 (2): 297-310

    Abstract

    Kaposi's sarcoma (KS) is the most common malignancy seen in association with AIDS. Important epidemiologic trends in the occurrence of AIDS-associated Kaposi's sarcoma (AIDS-KS) have been identified, and the molecular processes associated with the development of KS are being studied intensively. It is hoped that these studies will ultimately lead to an understanding of the etiology of the disease and to a rational approach to therapy. Treatment with conventional chemotherapy, radiation therapy, biologic therapy, and various local treatment modalities is effective for palliation of clinical problems associated with AIDS-KS, although the toxicities of these approaches may be problematic. Therapy for AIDS-KS must be individualized, with appropriate consideration given to the patient's overall clinical and immunologic status.

    View details for Web of Science ID A1991FD96100008

    View details for PubMedID 2022595

  • CRYOTHERAPY FOR CUTANEOUS KAPOSIS-SARCOMA (KS) ASSOCIATED WITH ACQUIRED-IMMUNE-DEFICIENCY-SYNDROME (AIDS) - A PHASE-II TRIAL JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Tappero, J. W., Berger, T. G., Kaplan, L. D., Volberding, P. A., Kahn, J. O. 1991; 4 (9): 839-846

    Abstract

    To assess the response and toxicity of liquid nitrogen cryotherapy for cutaneous lesions of Kaposi's sarcoma (KS) associated with AIDS, we evaluated 20 subjects with biopsy-proven KS in a phase II clinical trial. Subjects had two to four cutaneous KS indicator lesions treated with liquid nitrogen cyrotherapy. Treatment was repeated at 3 week intervals, allowing adequate healing time. On average, subjects received three treatments per lesion with a mean follow-up time of 11 weeks (range of 6-25 weeks). One treatment consisted of two freeze-thaw cycles, with thaw times ranging from 11 to 60 s per cycle. A complete response was observed in 80% of treated KS lesions and lasted a minimum of 6 weeks following the completion of therapy. Greater than 50% cosmetic improvement of KS was observed. Histopathology of treated lesions correlated poorly with cosmetic improvement. Response was not predicted by tolerance to zidovudine therapy, CD4+ cell count, presence of B symptoms, or previous chemotherapy. Subjects without prior history of opportunistic infection (OI) were more likely to have a better response than those with a prior history of OI. Subjects tolerated cryotherapy well. Blistering occurred frequently, but local pain was limited and relieved by acetaminophen. Secondary infection did not occur. Based on this study, we recommend cryotherapy to subjects with cutaneous KS lesions. Liquid nitrogen cryotherapy is easily applied as a primary therapy, and may also have a role in the treatment of cutaneous KS lesions that respond slowly or show incomplete cosmetic improvement with systemic therapies.

    View details for Web of Science ID A1991GD59700002

    View details for PubMedID 1895204

  • THE SAFETY AND PHARMACOKINETICS OF GLQ223 IN SUBJECTS WITH AIDS AND AIDS-RELATED COMPLEX - A PHASE-I STUDY AIDS Kahn, J. O., Kaplan, L. D., Gambertoglio, J. G., Bredesen, D., ARRI, C. J., Turin, L., KIBORT, T., Williams, R. L., Lifson, J. D., Volberding, P. A. 1990; 4 (12): 1197-1204

    Abstract

    A phase I dose-escalation study was performed to evaluate the safety and pharmacokinetics of a single intravenous infusion of GLQ223 in subjects with AIDS and AIDS-related complex (ARC). The active ingredient in GLQ223 is trichosanthin. Trichosanthin, imported from China, is the active drug in community-initiated treatment programs for patients with HIV infection. Eighteen subjects were enrolled, 10 with AIDS and eight with ARC. All subjects were monitored for tolerance and toxicity. Immunological and virological parameters were also followed. GLQ223 administration was not associated with notable toxicity with the exception of one subject who experienced a severe neurological adverse reaction. No consistent or sustained changes in CD4+ lymphocyte populations or HIV antigen levels were observed. Serum concentrations of GLQ223 that were comparable to concentrations shown to have antiviral activity in vitro were achieved transiently but may not have been maintained for a sufficient duration to exert antiretroviral effects. Further studies are indicated to determine pharmacodynamic properties of GLQ223, its optimal dosing schedule, and whether GLQ223 or related molecules will be useful in the treatment of HIV infection.

    View details for Web of Science ID A1990ER95000003

    View details for PubMedID 2088398

  • THE SAFETY AND PHARMACOKINETICS OF RECOMBINANT SOLUBLE CD4 (RCD4) IN SUBJECTS WITH THE ACQUIRED-IMMUNODEFICIENCY-SYNDROME (AIDS) AND AIDS-RELATED COMPLEX - A PHASE-1 STUDY ANNALS OF INTERNAL MEDICINE Kahn, J. O., Allan, J. D., HODGES, T. L., Kaplan, L. D., ARRI, C. J., FITCH, H. F., Izu, A. E., Mordenti, J., SHERWIN, S. A., Groopman, J. E., Volberding, P. A. 1990; 112 (4): 254-261

    Abstract

    To evaluate the safety and pharmacokinetics of recombinant, soluble human CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The protein rCD4 binds to envelope protein, gp120, of the human immunodeficiency virus (HIV) and blocks HIV infection of CD4 lymphocytes in vitro.Phase 1 trial with dose escalation.Two university-affiliated hospital clinics.Of 42 subjects enrolled, 29 had AIDS and 13 had AIDS-related complex.The rCD4 was administered by rapid intravenous infusion on day 1, followed by a 3-day washout, then once a day for 10 days, followed by a 7-day washout, and then three times a week for 8 weeks. Doses of 1, 10, 30, 100, and 300 micrograms/kg body weight per day of rCD4 were administered intravenously to 6 subjects at each dose level. Twelve additional patients received 300 micrograms/kg.d of rCD4: 6 by intramuscular and 6 by subcutaneous injection. All subjects were monitored for toxicity. Immunologic and virologic variables were also monitored. MEASUREMENTS andAdministration of rCD4 was not associated with important toxicity as determined by clinical monitoring or by serum chemistry, hematologic, or immunologic variables. No subjects required dose reduction or discontinuation of therapy due to rCD4-related toxicity. No consistent or sustained changes in CD4 lymphocyte populations or HIV antigen levels were observed. The volume of distribution of rCD4 was small, and clearance remained constant over the dose range studied. The bioavailability of intramuscular injection and subcutaneous injection was 51% and 45%, respectively.At the dose levels used in this study, rCD4 appears safe and well tolerated. Serum concentrations of rCD4 were achieved that were comparable to concentrations shown to have antiviral activity in vitro. Further studies are indicated to determine whether rCD4 or related molecules will be useful in treating HIV infection.

    View details for Web of Science ID A1990CN55400005

    View details for PubMedID 2297204

  • AIDS-associated Kaposi's sarcoma. AIDS clinical review Kahn, J. O. 1990: 115-128

    View details for PubMedID 1707293

  • INTRALESIONAL RECOMBINANT TUMOR NECROSIS FACTOR-ALPHA FOR AIDS-ASSOCIATED KAPOSIS SARCOMA - A RANDOMIZED, DOUBLE-BLIND TRIAL JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Kahn, J. O., Kaplan, L. D., Volberding, P. A., Ziegler, J. L., Crowe, S., SAKS, S. R., Abrams, D. I. 1989; 2 (3): 217-223

    Abstract

    The effect of recombinant tumor necrosis factor-alpha (rTNF), injected directly into the tumor, was evaluated in a Phase I/II study of 27 patients with AIDS-associated Kaposi's sarcoma (KS). The maximally tolerated intralesional dose was less than 100 micrograms/m2 and the recommended intralesional dose was 25 micrograms/m2. In a double-blind, randomized, placebo-controlled study, rTNF reduced the cross-sectional area of 15 of 16 (94%) of the injected KS lesions and caused complete disappearance of 3 of 16 (19%) lesions. Only injected lesions showed a response. Rigors and fever were common dose-dependent side effects and were attenuated by meperidine. There were no changes in human immunodeficiency virus (HIV) activity as determined by serum p24 antigen levels. While biologically active, the systemic toxicity of rTNF as well as the lack of distant antitumor effects in noninjected lesions limits its clinical usefulness under the conditions employed in this trial.

    View details for Web of Science ID A1989U691300001

    View details for PubMedID 2498507

Conference Proceedings


  • Postexposure prophylaxis for human immunodeficiency virus infection after sexual or injection drug use exposure: Identification and characterization of the source of exposure Roland, M. E., Martin, J. N., Grant, R. M., Hellmann, N. S., Bamberger, J. D., Katz, M. H., Chesney, M., Franses, K., Coates, T. J., Kahn, J. O. UNIV CHICAGO PRESS. 2001: 1608-1612

    Abstract

    In a nonrandomized study of nonoccupational postexposure prophylaxis (PEP), a cross-sectional evaluation of subjects who were the source of human immunodeficiency (HIV) exposure was performed to characterize partners of index subjects seeking nonoccupational PEP against HIV. Among 401 index subjects, 64 (16%) recruited a source subject. Those in a steady relationship and those who knew that the source subject was HIV antibody positive were more likely to recruit their source subject. Source subjects reported high rates of past (78%) and current (69%) antiretroviral use; 46% of those using antiretroviral drugs had detectable plasma HIV-1 RNA levels. Antiretroviral resistance was detected in many source subjects who reported any use of antiretrovirals and was rare among source subjects who reported no history of antiretroviral use. Clinicians often make treatment decisions on the basis of incomplete knowledge of the source subject's HIV status or antiretroviral treatment history. The treatment history, particularly nonuse of a class of antiretroviral drugs, can be used to predict drug resistance.

    View details for Web of Science ID 000172545000016

    View details for PubMedID 11740738

  • Prototype trial design for rapid dose selection of antiretroviral drugs: an example using emtricitabine (Coviracil) Rousseau, F. S., Kahn, J. O., Thompson, M., Mildvan, D., Shepp, D., Sommadossi, J. P., Delehanty, J., Simpson, J. N., Wang, L. H., Quinn, J. B., Wakeford, C., van der Horst, C. OXFORD UNIV PRESS. 2001: 507-513

    Abstract

    Antiretroviral monotherapy for initial drug characterization risks the selection of resistant virus, yet monotherapy is the only setting where many fundamental properties of a new drug can be reliably determined. Using data on viral replication kinetics and dynamics, we designed an accelerated (14 day) open-label study of single agent emtricitabine (formerly known as FTC)--a nucleoside reverse transcriptase inhibitor--to select a dosing regimen for further therapeutic study. Five regimens (25 mg bd, 100 mg od, 200 mg od, 100 mg bd and 200 mg bd) were evaluated in HIV-1-infected subjects over a 14 day dosing period to determine the optimal dose and pharmacokinetics. Serial blood samples for virological, pharmacokinetic and intracellular FTC-triphosphate measurements were drawn frequently. A dose-response relationship for the antiviral activity of emtricitabine was established, with total daily doses of 200 mg or more producing the greatest median HIV-1 viral load suppression: 1.72-1.92 log10. Based on virological outcomes, dose-response analysis and intracellular triphosphate levels, a once-daily dose of 200 mg was selected for further long-term clinical study. Adverse events possibly related to emtricitabine were unremarkable. The antiviral activity of emtricitabine correlated well with intracellular FTC-triphosphate concentrations. This study design is a safe, useful tool for early dose selection for drugs with potent antiretroviral activity and linear pharmacokinetics.

    View details for Web of Science ID 000171877700006

    View details for PubMedID 11581229

  • Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: The San Francisco PEP study Kahn, J. O., Martin, J. N., Roland, M. E., Bamberger, J. D., Chesney, M., Chambers, D., Franses, K., Coates, T. J., Hatz, M. H. UNIV CHICAGO PRESS. 2001: 707-714

    Abstract

    The feasibility of providing postexposure prophylaxis (PEP) after sexual or injection drug use exposures to human immunodeficiency virus (HIV) was evaluated. PEP was provided within 72 h to individuals with exposures from partners known to have or to be at risk for HIV infection. PEP consisted of 4 weeks of antiretroviral medications and individually tailored risk-reduction and medication-adherence counseling. Among 401 participants seeking PEP, sexual exposures were most common (94%; n=375). Among sexual exposures, receptive (40%) and insertive (27%) anal intercourse were the most common sexual acts. The median time from exposure to treatment was 33 h. Ninety-seven percent of participants were treated exclusively with dual reverse-transcriptase inhibitors, and 78% completed the 4-week treatment. Six months after the exposure, no participant developed HIV antibodies, although a second PEP course for a subsequent exposure was provided to 12%. PEP, after nonoccupational HIV exposure, is feasible for persons at risk for HIV infection.

    View details for Web of Science ID 000166836500004

    View details for PubMedID 11181146

  • Initial treatment for HIV infection - When, why, and with what? Kahn, J. O. KLUWER ACADEMIC/PLENUM PUBL. 1999: 229-237

    View details for Web of Science ID 000082968200022

    View details for PubMedID 10549395

  • The clinical use of didanosine Kahn, J. PLENUM PRESS DIV PLENUM PUBLISHING CORP. 1996: 245-256

    View details for Web of Science ID A1996BF30J00022

    View details for PubMedID 8815689

  • CD4 IMMUNOADHESINS IN ANTI-HIV THERAPY - NEW DEVELOPMENTS Chamow, S. M., Duliege, A. M., Ammann, A., Kahn, J. O., Allen, J. D., Eichberg, J. W., Byrn, R. A., Capon, D. J., WARD, R. H., Ashkenazi, A. JOHN WILEY & SONS INC. 1992: 69-72

    Abstract

    CD4, the cell-surface receptor for the human immunodeficiency virus (HIV), is a member of the immunoglobulin (Ig) gene superfamily. It contains 4 extracellular sequences homologous to Ig variable domains, the first of which (V1) is sufficient for binding to HIV. To develop CD4 as an anti-HIV therapeutic, we engineered a CD4 immunoadhesin (CD4-IgG)--a fusion protein containing the V1 and V2 domains of CD4 with the hinge and Fc regions of human Ig heavy chain. A chimeric protein of this type has several advantages compared to the soluble receptor, including a greatly extended in vivo half-life and greater avidity for HIV; moreover, like an antibody, it performs effector functions via its Fc domains, such as complement activation and antibody-dependent cell-mediated cytotoxicity. In vivo experiments show that CD4-IgG protects against HIV-I IIIB infection of chimpanzees when administered prior to viral challenge. In addition, CD4-IgG is transferred efficiently across the placenta from mother to fetus in rhesus monkeys. To evaluate its safety in humans, we conducted a phase-I clinical trial in adult patients with AIDS and AIDS-related complex. We found that, in a total of 16 patients, administration of CD4-IgG was well tolerated at doses up to 1000 micrograms/kg of body weight, with no important clinical or immunological toxicities noted. Given its unique properties, particularly the ability of CD4-IgG to cross the placenta, we plan to focus future clinical efforts on preventing infection of newborns via maternal-fetal transfer of HIV.

    View details for Web of Science ID A1992JY98000018

    View details for PubMedID 1428410

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